Coated packaging

ABSTRACT

A vessel has an interior surface facing a lumen. The interior surface includes a tie coating or layer, a barrier coating or layer, and a pH protective coating or layer. The tie coating or layer can comprise SiOxCy or SiNxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3. The barrier coating or layer can comprise SiOx, wherein x is from 1.5 to 2.9. The barrier coating or layer reduces the ingress of atmospheric gas into the lumen. The pH protective coating or layer can comprise SiOxCy or SiNxCy, as well. In an embodiment, in the presence of a fluid composition contained in the lumen and having a pH between 5 and 9, the calculated shelf life of the package can be more than six months at a storage temperature of 4° C.

This application is a continuation of U.S. application Ser. No.14/774,073, filed Sep. 9, 2015, which is a 371 of InternationalApplication No. PCT/US2014/023813 filed Mar. 11, 2014, which claimspriority to U.S. Provisional Applications 61/776,733, filed Mar. 11,2013, and 61/800,746, filed Mar. 15, 2013. The entire specification andall the drawings of each of these provisional applications isincorporated here by reference to provide continuity of disclosure.

The specification and drawings of U.S. Pat. No. 7,985,188 areincorporated here by reference in their entirety. That patent describesapparatus, vessels, precursors, coatings or layers and methods (inparticular coating methods and test methods for examining the coatingsor layers) which can generally be used in performing the presentinvention, unless stated otherwise herein. They also describe SiO_(x)barrier coatings or layers and SiO_(x)C_(y) coatings to which referenceis made herein.

FIELD OF THE INVENTION

The present invention relates to the technical field of barrier coatedsurfaces, for example interior surfaces of pharmaceutical packages orother vessels for storing or other contact with fluids. Examples ofsuitable fluids include foods, nutritional supplements, drugs,inhalation anaesthetics, diagnostic test materials, biologically activecompounds or body fluids, for example blood. The present invention alsorelates to a pharmaceutical package or other vessel and to a method formaking a pharmaceutical package with a pH protective coating or layerbetween the contents and the barrier coating or layer. The presentinvention also relates more generally to medical articles, includingarticles other than packages or vessels, for example catheters.

The present disclosure also relates to improved methods for processingpharmaceutical packages or other vessels, for example multiple identicalpharmaceutical packages or other vessels used for pharmaceuticalpreparation storage and delivery, venipuncture and other medical samplecollection, and other purposes.

The resulting packages are also claimed. Such pharmaceutical packages orother vessels are used in large numbers for these purposes, and must berelatively economical to manufacture and yet highly reliable in storageand use.

BACKGROUND OF THE INVENTION

One important consideration in manufacturing pharmaceutical packages orother vessels for storing or other contact with fluids, for examplevials and pre-filled syringes, is that the contents of thepharmaceutical package or other vessel desirably will have a substantialshelf life. During this shelf life, it is important to isolate thematerial filling the pharmaceutical package or other vessel from thevessel wall containing it, or from barrier layers or other functionallayers applied to the pharmaceutical package or other vessel wall toavoid leaching material from the pharmaceutical package or other vesselwall, barrier layer, or other functional layers into the prefilledcontents or vice versa.

The traditional glass pharmaceutical packages or other vessels are proneto breakage or degradation during manufacture, filling operations,shipping and use, which means that glass particulates may enter thedrug. The presence of glass particles has led to many FDA WarningLetters and to product recalls.

As a result, some companies have turned to plastic pharmaceuticalpackages or other vessels, which provide greater dimensional toleranceand less breakage than glass, but its use for primary pharmaceuticalpackaging remains limited due to its gas (oxygen) permeability: Plasticallows small molecule gases to permeate into (or out of) the article.The permeability of plastics to gases is significantly greater than thatof glass and, in many cases (as with oxygen-sensitive drugs such asepinephrine), plastics have been unacceptable for that reason.

The problem of permeability has been addressed by adding a barriercoating or layer to the plastic pharmaceutical package where it contactsfluid contents of the package. One such barrier layer is a very thincoating of SiO_(x), as defined below, applied by plasma enhancedchemical vapor deposition. But, current SiO_(x) barrier layers depositedon a package by PECVD are etched off by aqueous contents of the packagehaving pH-values greater than 4, particularly at higher pH values. Thisreduces the useful shelf life of the package as its barrier efficacy isreduced.

SUMMARY OF THE INVENTION

An aspect of the invention is a vessel comprising or consisting of: athermoplastic wall having an interior surface enclosing at least aportion of a lumen.

The tie coating or layer comprises or consists of SiO_(x)C_(y)H_(z) orSiN_(x)C_(y)H_(z) in which x is from about 0.5 to about 2.4 as measuredby X-ray photoelectron spectroscopy (XPS), y is from about 0.6 to about3 as measured by XPS, and z is from about 2 to about 9 as measured by atleast one of Rutherford backscattering spectrometry (RBS) or hydrogenforward scattering (HFS). The tie coating or layer has an outer surfacefacing the wall surface and an interior surface.

The barrier coating or layer comprises or consists of SiO_(x), in whichx is from about 1.5 to about 2.9 as measured by XPS. The barrier coatingor layer is positioned between the interior surface of the tie coatingor layer and the lumen.

The pH protective coating or layer comprises or consists ofSiO_(x)C_(y)H_(z), in which x is from about 0.5 to about 2.4 as measuredby XPS, y is from about 0.6 to about 3 as measured by XPS, and z is fromabout 2 to about 9 as measured by at least one of RBS or HFS. The pHprotective coating or layer is positioned between the barrier coating orlayer and the lumen.

The pH protective coating or layer and tie coating or layer together areeffective to keep the barrier coating or layer at least substantiallyundissolved as a result of attack by a fluid contained in the lumenhaving a pH greater than 5 for a period of at least six months.

Another aspect of the invention is the use of such a vessel for storinga fluid having a pH greater than 5.

Still another aspect of the invention is a process for making such avessel comprising or consisting of the steps of forming a tie coating orlayer on the vessel interior wall; forming a barrier coating or layerover at least a portion of the tie coating or layer; and forming a pHprotective coating or layer positioned between the barrier coating orlayer and the lumen.

The pH protective coating or layer and tie coating or layer together areeffective to keep the barrier coating or layer at least substantiallyundissolved as a result of attack by a fluid contained in the lumenhaving a pH greater than 5 for a period of at least six months.

Even another aspect of the invention is a vessel processing systemadapted for making such a vessel.

In any embodiment of the invention, the tie coating or layer optionallycan be applied by plasma enhanced chemical vapor deposition (PECVD).

In any embodiment of the invention, the barrier coating or layeroptionally can be applied by PECVD.

In any embodiment of the invention, the pH protective coating or layeroptionally can be applied by PECVD.

In any embodiment of the invention, the vessel can comprise or consistof a syringe barrel, a vial, cartridge or a blister package.

In any embodiment of the invention, at least a portion of thethermoplastic wall comprises or consists of:

-   -   a polyolefin,    -   a polyvinylalcohol    -   a polymethacrylate ether    -   a polyacrylic acid    -   a polyamide    -   a polyimide    -   a polysulfone    -   a polylactic acid    -   a cyclic olefin polymer or copolymer    -   a polyester    -   a combination of a polyolefin and a polyester or    -   a combination of any one of the foregoing.

In any embodiment of the invention, for the pH protective coating orlayer, x optionally can be from about 1 to about 2 as measured by XPS, yoptionally can be from about 0.6 to about 1.5 as measured by XPS, and zoptionally can be from about 2 to about 5 as measured by RBS or HFS.

In any embodiment of the invention, the pH protective coating or layerhas been applied by PECVD of a precursor feed comprising anorganosilicon precursor.

In any embodiment of the invention, the organosilicon precursorcomprises or consists of hexamethyldisiloxane (HMDSO), trimethylsilane(TriMS), tetramethylsilane (TetraMS), tetramethyldisiloxane (TMDSO),octamethylcyclotetrasiloxane (OMCTS) or a combination of two or more ofthem.

In any embodiment of the invention, the precursor feed for the pHprotective coating or layer comprises or consists of:

-   -   from 0.5 to 10 standard volumes of the organosilicon precursor;    -   from 0.1 to 10 standard volumes of oxygen; and    -   from 1 to 100 standard volumes of a carrier gas.

In any embodiment of the invention, the pH protective coating or layeroptionally can be from about 10 to about 1000 nm thick.

In any embodiment of the invention, the pH protective coating or layercontacting the fluid composition optionally can be from about 10 toabout 1000 nm thick after contact with a fluid contained in the lumenhaving a pH greater than 5 for a period of two years.

In any embodiment of the invention, the rate of erosion of the pHprotective coating or layer, if directly contacted by a fluid containedin the lumen having a pH greater than 5, optionally can be less than 20%of the rate of erosion of the barrier coating or layer, if directlycontacted by the same fluid under the same conditions.

In any embodiment of the invention, The vessel of any preceding claim,having a shelf life, while directly contacted by a fluid contained inthe lumen having a pH greater than 5, of at least two years.

In any embodiment of the invention, the shelf life optionally can bebased on storage of the vessel containing the fluid at 20° C.

In any embodiment of the invention, the shelf life optionally can bebased on storage of the vessel containing the fluid at 40° C.

In any embodiment of the invention, a fluid contained in the lumenhaving a pH greater than 5 optionally can remove the pH protectivecoating or layer at a rate of 1 nm or less of pH protective coating orlayer thickness per 88 hours of contact with the fluid.

In any embodiment of the invention, an FTIR absorbance spectrum of thepH protective coating or layer optionally can have a ratio greater than0.75 between:

-   -   the maximum amplitude of the Si—O—Si symmetrical stretch peak        between about 1000 and 1040 cm-1, and    -   the maximum amplitude of the Si—O—Si asymmetric stretch peak        between about 1060 and about 1100 cm-1.

In any embodiment of the invention, the silicon dissolution rate by a 50mM potassium phosphate buffer diluted in water for injection, adjustedto pH 8 with concentrated nitric acid, and containing 0.2 wt. %polysorbate-80 surfactant, from the vessel optionally can be less than170 ppb/day.

In any embodiment of the invention, the total silicon content of the pHprotective coating or layer, barrier coating or layer, and tie coatingor layer, as measured by dissolution of the pH protective coating orlayer, barrier coating or layer, and tie coating or layer into 0.1 Npotassium hydroxide aqueous solution at 40° C. from the vessel,optionally can be less than 66 ppm.

In any embodiment of the invention, the calculated shelf life optionallycan be more than 2 years.

In any embodiment of the invention, after formation of a groove byfocused ion beam through the pH protective coating or layer, the barriercoating or layer, the tie coating or layer, and into the lumen wall, andexposure of the groove with 1N aqueous potassium hydroxide (KOH)solution maintained at 40° C. in the lumen for 6.5 hours, the barriercoating or layer optionally can be detectable by XPS and optionally canhave atomic percentages of oxygen and silicon within 10 atomic percentof their values before treatment of the groove with the KOH solution.

In any embodiment of the invention, the pH protective coating or layeroptionally can show an O-Parameter measured with attenuated totalreflection (ATR) of less than 0.4, measured as:

${O\text{-}{Parameter}} = \frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}\text{-}1}{{Maximum}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu}{from}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{{cm}^{- 1}.}}$

In any embodiment of the invention, the pH protective coating or layeroptionally can show an N-Parameter measured with attenuated totalreflection (ATR) of less than 0.7, measured as:

${N\text{-}{Parameter}} = \frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 840\mspace{14mu}{cm}^{- 1}}{{Intensity}\mspace{14mu}{at}\mspace{14mu} 799\mspace{14mu}{{cm}^{- 1}.}}$

In any embodiment of the invention, the pH protective coating or layeroptionally can be applied by PECVD at a power level per of more than22,000 kJ/kg of mass of polymerizing gases in the PECVD reactionchamber.

In any embodiment of the invention, the pH protective coating or layeroptionally can be applied by PECVD at a power level per of from 1 to 200W.

In any embodiment of the invention, for formation of the pH protectivecoating or layer the ratio of the electrode power applied by PECVD tothe plasma volume optionally can be from 5 W/ml to 75 W/ml.

In any embodiment of the invention, for the tie coating or layer, xoptionally can be from about 1 to about 2 as measured by X-rayphotoelectron spectroscopy (XPS), y optionally can be from about 0.6 toabout 1.5 as measured by XPS, and z optionally can be from about 2 toabout 5 as measured by Rutherford backscattering spectrometry (RBS) orhydrogen forward scattering (HFS).

In any embodiment of the invention, the tie coating or layer optionallycan be applied by PECVD of a precursor feed comprising an organosiliconprecursor.

In any embodiment of the invention, the organosilicon precursoroptionally can be tetramethylsilane (TetraMS), trimethylsilane (TriMS),hexamethyldisiloxane (HMDSO), octamethylcyclotetrasiloxane (OMCTS),tetramethyldisiloxane (TMDSO), or a combination of two or more of these.

In any embodiment of the invention, the precursor feed for the tiecoating or layer optionally comprises or consists of:

-   -   from 0.5 to 10 standard volumes of the organosilicon precursor;    -   from 0.1 to 10 standard volumes of oxygen; and    -   from 1 to 120 standard volumes of a carrier gas.

In any embodiment of the invention, the tie coating or layer optionallycan be on average from about 5 to about 200 nm thick.

Any embodiment of the invention optionally can further comprise alubricity coating or layer applied between the pH protective coating orlayer and the lumen.

In any embodiment of the invention, the vessel of any preceding claimoptionally can be a prefilled syringe having a syringe barrel coated onits interior wall with the tie coating or layer, barrier coating orlayer, and pH protective coating or layer. It optionally can furtherhave a plunger seated in the barrel.

In any embodiment of the invention, the vessel of any preceding claimoptionally can contain a pharmaceutical composition having a pH greaterthan 5 contained in the lumen, the prefilled syringe having a shelf lifeof at least six months.

In any embodiment of the invention, the vessel of claim 34 optionallycan further comprise a lubricity coating or layer on at least a portionof the plunger and/or syringe barrel wall.

Many additional and alternative aspects and embodiments of the inventionare also contemplated, and are described in the specification and claimsthat follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic sectional view of a vessel according to anyembodiment of the invention.

FIG. 2 is an enlarged detail view of a portion of the vessel wall andcoatings of FIG. 1.

FIG. 3 is a schematic view of a pharmaceutical package in the form of asyringe barrel as the vessel of FIGS. 1 and 2, containing a fluid andclosed with a closure in the form of a plunger.

FIG. 4 is a schematic view of a pharmaceutical package in the form of avial as the vessel of FIGS. 1 and 2 containing a fluid and closed with aclosure.

FIG. 5 is a schematic view of a pharmaceutical package in the form of ablister package as the vessel of FIGS. 1 and 2 containing a fluid andclosed with a closure in the form of a coated sheet defining anadditional vessel wall.

FIG. 6 is a plot of silicon dissolution versus exposure time at pH 6 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall.

FIG. 7 is a plot of silicon dissolution versus exposure time at pH 7 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall.

FIG. 8 is a plot of silicon dissolution versus exposure time at pH 8 fora glass container versus a plastic container having an SiO_(x) barrierlayer coated in the inside wall.

FIG. 9 is a plot of the SiO_(x) coating thickness necessary initially toleave a 30 nm residual coating thickness when stored with solutions atdifferent nominal pH values from 3 to 9.

FIG. 10 shows the silicon dissolution rates at pH 8 and 40° C. ofvarious PECVD coatings.

FIG. 11 is a plot of the ratio of Si—O—Si symmetric/asymmetricstretching mode versus energy input per unit mass (W/FM or KJ/kg) of aPECVD coating using as the reactive precursor gases OMCTS and oxygen.

FIG. 12 is a plot of silicon shelf life (days) versus energy input perunit mass (W/FM or KJ/kg) of a PECVD coating using as the reactiveprecursor gases OMCTS and oxygen.

FIG. 13 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 14 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 15 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 16 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 17 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating, originally presented as FIG. 5of U.S. Pat. No. 8,067,070, annotated to show the calculation of theO-Parameter referred to in that patent.

FIG. 18 is a schematic view of a syringe with a trilayer coatingaccording to FIGS. 1, 2, and 3, showing a cylindrical region andspecific points where data was taken.

FIG. 19 is a Trimetric map of the overall trilayer coating thicknessversus position in the cylindrical region of a syringe illustrated byFIGS. 18, 1, 2, and 3.

FIG. 20 is a photomicrograhic sectional view showing the substrate andcoatings of the trilayer coating at position 2 shown in FIG. 18.

FIG. 21 is another Trimetric map of the overall trilayer coatingthickness versus position in the cylindrical region of a syringeillustrated by FIGS. 18, 1, 2, and 3.

FIG. 22 is a plot of coating thickness, representing the same coating asFIG. 21, at Positions 1, 2, 3, and 4 shown in FIG. 18.

FIG. 23 is a schematic illustration of a syringe, showing points on itssurface where measurements were made in a working example.

FIG. 24 is a photograph showing the benefit of the present trilayercoating in preventing pinholes after attack by an alkaline reagent, asdiscussed in the working examples.

FIG. 24A is an enlarged detail view of the indicated portion of FIG. 24.

FIG. 25 is a schematic sectional view of a lateral trench cut into avessel wall and coating set as shown in FIG. 2 for Example NN.

FIG. 26 is a photomicrographic plan view of the trench of FIG. 25 beforeKOH treatment, as referred to in Example NN.

FIG. 27 is a photomicrographic plan view of the trench of FIG. 25 after3 hours of KOH treatment, as referred to in Example NN.

FIG. 28 is a photomicrographic plan view of the trench of FIG. 25 after6.5 hours of KOH treatment, as referred to in Example NN.

FIG. 29 is an XPS plot resulting from a lateral scan across the trenchof FIG. 25 before KOH treatment, as referred to in Example NN.

FIG. 30 is an XPS plot resulting from a lateral scan across the trenchof FIG. 25 after 3 hours of KOH treatment, as referred to in Example NN.

FIG. 31 is an XPS plot resulting from a lateral scan across the trenchof FIG. 25 after 6 hours of KOH treatment, as referred to in Example NN.

FIG. 32 is a schematic view of a system for making the vessels andcarrying out processes for making them.

The following reference characters are used in the drawing figures:

210 Pharmaceutical package 212 Lumen 214 Wall 216 Outer surface 218Fluid 220 Interior surface (of 288) 222 Outer surface (of 288) 224Interior surface (of 286) 226 Outer surface (of 286) 228 Vial 230Blister package 250 Syringe barrel 252 Syringe 254 Inner or interiorsurface (of 250) 256 Back end (of 250) 258 Plunger (of 252) (relativelysliding part) 259 Lubricant 260 Front end (of 250) 262 Closure 264 Inneror interior surface (of 262) 268 Vessel 270 Closure 272 Interior facingsurface 274 Lumen 276 Wall-contacting surface 278 Inner or interiorsurface (of 280) 280 Vessel wall 281 Lubricity coating or layer 282Stopper 283 PH protective coating or layer 284 Shield 285 Vessel coatingor layer set 286 pH protective coating or layer 287 Deposit of lubricant288 Barrier layer 289 Tie coating or layer 290 Apparatus for coating,for example, 250 292 Inner or interior surface (of 294) 294 Restrictedopening (of 250) 296 Processing vessel 298 Outer surface (of 250) 302Tie coater 304 Barrier coater 306 pH protective coater 308 Fluid filler310 Fluid supply 312 Closure installer 314 Closure supply

In the context of the present invention, the following definitions andabbreviations are used:

The term “at least” in the context of the present invention means “equalor more” than the integer following the term. The word “comprising” doesnot exclude other elements or steps, and the indefinite article “a” or“an” does not exclude a plurality unless indicated otherwise. Whenever aparameter range is indicated, it is intended to disclose the parametervalues given as limits of the range and all values of the parameterfalling within said range.

“First” and “second” or similar references to, for example, deposits oflubricant, processing stations or processing devices refer to theminimum number of deposits, processing stations or devices that arepresent, but do not necessarily represent the order or total number ofdeposits, processing stations and devices or require additionaldeposits, processing stations and devices beyond the stated number.These terms do not limit the number of processing stations or theparticular processing carried out at the respective stations. Forexample, a “first” deposit in the context of this specification can beeither the only deposit or any one of plural deposits, withoutlimitation. In other words, recitation of a “first” deposit allows butdoes not require an embodiment that also has a second or furtherdeposit.

For purposes of the present invention, an “organosilicon precursor” is acompound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogenatom and an organic carbon atom (an organic carbon atom being a carbonatom bonded to at least one hydrogen atom). A volatile organosiliconprecursor, defined as such a precursor that can be supplied as a vaporin a PECVD apparatus, is an optional organosilicon precursor.Optionally, the organosilicon precursor is selected from the groupconsisting of a linear siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linearsilazane, a monocyclic silazane, a polycyclic silazane, apolysilsesquiazane, and a combination of any two or more of theseprecursors.

The feed amounts of PECVD precursors, gaseous reactant or process gases,and carrier gas are sometimes expressed in “standard volumes” in thespecification and claims. The standard volume of a charge or other fixedamount of gas is the volume the fixed amount of the gas would occupy ata standard temperature and pressure (without regard to the actualtemperature and pressure of delivery). Standard volumes can be measuredusing different units of volume, and still be within the scope of thepresent disclosure and claims. For example, the same fixed amount of gascould be expressed as the number of standard cubic centimeters, thenumber of standard cubic meters, or the number of standard cubic feet.Standard volumes can also be defined using different standardtemperatures and pressures, and still be within the scope of the presentdisclosure and claims. For example, the standard temperature might be 0°C. and the standard pressure might be 760 Torr (as is conventional), orthe standard temperature might be 20° C. and the standard pressure mightbe 1 Torr. But whatever standard is used in a given case, when comparingrelative amounts of two or more different gases without specifyingparticular parameters, the same units of volume, standard temperature,and standard pressure are to be used relative to each gas, unlessotherwise indicated.

The corresponding feed rates of PECVD precursors, gaseous reactant orprocess gases, and carrier gas are expressed in standard volumes perunit of time in the specification. For example, in the working examplesthe flow rates are expressed as standard cubic centimeters per minute,abbreviated as sccm. As with the other parameters, other units of timecan be used, such as seconds or hours, but consistent parameters are tobe used when comparing the flow rates of two or more gases, unlessotherwise indicated.

A “vessel” in the context of the present invention can be any type ofvessel with at least one opening and a wall defining an inner orinterior surface. The substrate can be the wall of a vessel having alumen. Though the invention is not necessarily limited to pharmaceuticalpackages or other vessels of a particular volume, pharmaceuticalpackages or other vessels are contemplated in which the lumen has a voidvolume of from 0.5 to 50 mL, optionally from 1 to 10 mL, optionally from0.5 to 5 mL, optionally from 1 to 3 mL. The substrate surface can bepart or all of the inner or interior surface of a vessel having at leastone opening and an inner or interior surface. Some examples of apharmaceutical package include, but are not limited to, a vial, aplastic-coated vial, a syringe, a plastic coated syringe, a blisterpack, an ampoule, a plastic coated ampoule, a cartridge, a bottle, aplastic coated bottle, a pouch, a pump, a sprayer, a stopper, a needle,a plunger, a cap, a stent, a catheter or an implant.

The term “at least” in the context of the present invention means “equalor more” than the integer following the term. Thus, a vessel in thecontext of the present invention has one or more openings. One or twoopenings, like the openings of a sample tube (one opening) or a syringebarrel (two openings) are preferred. If the vessel has two openings,they can be of same or different size. If there is more than oneopening, one opening can be used for the gas inlet for a PECVD coatingmethod according to the present invention, while the other openings areeither capped or open. A vessel according to the present invention canbe a sample tube, for example for collecting or storing biologicalfluids like blood or urine, a syringe (or a part thereof, for example asyringe barrel) for storing or delivering a biologically active compoundor composition, for example a medicament or pharmaceutical composition,a vial for storing biological materials or biologically active compoundsor compositions, a pipe, for example a catheter for transportingbiological materials or biologically active compounds or compositions,or a cuvette for holding fluids, for example for holding biologicalmaterials or biologically active compounds or compositions.

A vessel can be of any shape, a vessel having a substantiallycylindrical wall adjacent to at least one of its open ends beingpreferred. Generally, the interior wall of the vessel is cylindricallyshaped, like, for example in a sample tube or a syringe barrel. Sampletubes and syringes or their parts (for example syringe barrels) arecontemplated.

A “hydrophobic layer” in the context of the present invention means thatthe coating or layer lowers the wetting tension of a surface coated withthe coating or layer, compared to the corresponding uncoated surface.Hydrophobicity is thus a function of both the uncoated substrate and thecoating or layer. The same applies with appropriate alterations forother contexts wherein the term “hydrophobic” is used. The term“hydrophilic” means the opposite, i.e. that the wetting tension isincreased compared to reference sample. The present hydrophobic layersare primarily defined by their hydrophobicity and the process conditionsproviding hydrophobicity.

In the empirical composition Si_(w)O_(x)C_(y)H_(z) or the equivalentcomposition SiO_(x)C_(y), the values of w, x, y, and z used throughoutthis specification should be understood as ratios or an empiricalformula (for example for a coating or layer), rather than as a limit onthe number or type of atoms in a molecule. For example,octamethylcyclotetrasiloxane, which has the molecular compositionSi₄O₄C₈H₂₄, can be described by the following empirical formula, arrivedat by dividing each of w, x, y, and z in the molecular formula by 4, thelargest common factor: Si₁O₁C₂H₆. The values of w, x, y, and z are alsonot limited to integers. For example, (acyclic) octamethyltrisiloxane,molecular composition Si₃O₂C₈H₂₄, is reducible to Si₁O_(0.67)C_(2.67)H₈.Also, although SiO_(x)C_(y)H_(z) is described as equivalent toSiO_(x)C_(y), it is not necessary to show the presence of hydrogen inany proportion to show the presence of SiO_(x)C_(y).

“Wetting tension” is a specific measure for the hydrophobicity orhydrophilicity of a surface. An optional wetting tension measurementmethod in the context of the present invention is ASTM D 2578 or amodification of the method described in ASTM D 2578. This method usesstandard wetting tension solutions (called dyne solutions) to determinethe solution that comes nearest to wetting a plastic film surface forexactly two seconds. This is the film's wetting tension. The procedureutilized is varied herein from ASTM D 2578 in that the substrates arenot flat plastic films, but are tubes made according to the Protocol forForming PET Tube and (except for controls) coated according to theProtocol for coating Tube Interior with Hydrophobic Coating or Layer(see Example 9 of EP2251671 A2).

The atomic ratios of silicon, oxygen, and carbon can be determined byXPS. The atomic ratio of H atoms cannot be measured by XPS, which doesnot detect hydrogen. Optionally, the proportion of H atoms can bedetermined separately, for example by Rutherford backscattering orhydrogen forward scattering, preferably the former. Also, unlessotherwise indicated here, the value of w is normalized to 1, and thesubscript w is then conventionally omitted. The coating or layer maythus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z), for examplewhere w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 toabout 3, and z is from about 2 to about 9. The same coating or layer,with the same determination of w, x, and y, may thus in another aspecthave the formula SiO_(x)C_(y), for example where x is from about 0.5 toabout 2.4, y is from about 0.6 to about 3, and w and z are omitted.Typically, such coating or layer would hence contain 36% to 41% carbonnormalized to 100% carbon plus oxygen plus silicon.

The term “syringe” is broadly defined to include cartridges, injection“pens,” and other types of barrels or reservoirs adapted to be assembledwith one or more other components to provide a functional syringe.“Syringe” is also broadly defined to include related articles such asauto-injectors, which provide a mechanism for dispensing the contents.

A coating or layer or treatment is defined as “hydrophobic” if it lowersthe wetting tension of a surface, compared to the corresponding uncoatedor untreated surface. Hydrophobicity is thus a function of both theuntreated substrate and the treatment.

the word “comprising” does not exclude other elements or steps,

the indefinite article “a” or “an” does not exclude a plurality.

DETAILED DESCRIPTION

The present invention will now be described more fully, with referenceto the accompanying drawings, in which several embodiments are shown.This invention can, however, be embodied in many different forms andshould not be construed as limited to the embodiments set forth here.Rather, these embodiments are examples of the invention, which has thefull scope indicated by the language of the claims. Like numbers referto like or corresponding elements throughout. The following disclosurerelates to all embodiments unless specifically limited to a certainembodiment.

Referring to FIGS. 1 and 2, a vessel, here in the form of apharmaceutical package 210 is shown. Several non-limiting examples ofsuch vessels are a syringe barrel, a vial, a blister pack or package, anampoule, a cartridge, a bottle, a pouch, a pump, a sprayer, a stopper, aneedle, a plunger, a cap, a stent, a catheter or an implant, or anyother type of container or conduit for a fluid.

The vessel 210 of FIGS. 1 and 2 has a lumen 212 defined at least in partby a wall 214. At least a portion of the wall 214 optionally comprises acyclic olefin polymer. More generally, the suitable materials for thewall 214 of the vessel 250 include a polyolefin (for example a cyclicolefin polymer, a cyclic olefin copolymer, or polypropylene), apolyester, for example polyethylene terephthalate, a polycarbonate, orany combination or copolymer of any of these. Optionally, at least aportion of the wall 214 of the vessel 250 comprises or consistsessentially of glass, for example borosilicate glass. A combination ofany two or more of the materials in this paragraph can also be used.

The wall 214 has an interior surface facing the lumen, an outer surface,and a vessel coating set 285 on at least a portion of the wall 214facing the lumen 212. The interior surface comprises a tie coating orlayer 289, a barrier coating or layer 288, and a pH protective coatingor layer 286. This embodiment of the vessel coating or layer set 285 issometimes known as a “trilayer coating” in which the barrier coating orlayer 288 of SiO_(x) optionally is protected against contents having apH otherwise high enough to remove it by being sandwiched between the pHprotective coating or layer 286 and the tie coating or layer 289, eachan organic layer of SiO_(x)C_(y) as defined in this specification.

FIGS. 1 and 2 show a vessel having at least a single opening, and shouldbe understood to include a vessel having two or more openings, such as asyringe, or a vessel having no openings, such as a pouch, blister pack,or ampoule.

Tie Coating or Layer

Referring to FIGS. 1 and 2, the tie coating or layer 289 is provided,sometimes referred to as an adhesion coating or layer. The tie coatingor layer 289 optionally functions to improve adhesion of a barriercoating or layer 288 to a substrate, in particular a thermoplasticsubstrate, although a tie layer can be used to improve adhesion to aglass substrate or to another coating or layer.

Optionally, the tie coating or layer 289 improves adhesion of thebarrier coating or layer 288 to the substrate or wall 214. For example,the tie coating or layer 289, also referred to as an adhesion layer orcoating, can be applied to the substrate and the barrier layer can beapplied to the adhesion layer to improve adhesion of the barrier layeror coating to the substrate. Optionally, the adhesion or tie coating orlayer 289 is also believed to relieve stress on the barrier coating orlayer 288, making the barrier layer less subject to damage from thermalexpansion or contraction or mechanical shock.

Optionally, the tie coating or layer 289 applied under a barrier coatingor layer 288 can improve the function of a pH protective coating orlayer 286 applied over the barrier coating or layer 288.

Optionally, the adhesion or tie coating or layer 289 is also believed todecouple defects between the barrier coating or layer 288 and the COPsubstrate. This is believed to occur because any pinholes or otherdefects that may be formed when the adhesion or tie coating or layer 289is applied tend not to be continued when the barrier coating or layer288 is applied, so the pinholes or other defects in one coating do notline up with defects in the other. Optionally, the adhesion or tiecoating or layer 289 has some efficacy as a barrier layer, so even adefect providing a leakage path extending through the barrier coating orlayer 289 is blocked by the adhesion or tie coating or layer 289.

Optionally, the tie coating or layer 289 comprises SiO_(x)C_(y) orSiN_(x)C_(y), preferably can be composed of, comprise, or consistessentially of SiO_(x)C_(y), wherein x is from about 0.5 to about 2.4and y is from about 0.6 to about 3. The atomic ratios of Si, O, and C inthe tie coating or layer 289 optionally can be:

Si 100:O 50-150:C 90-200 (i.e. x=0.5 to 1.5, y=0.9 to 2);

Si 100:O 70-130:C 90-200 (i.e. x=0.7 to 1.3, y=0.9 to 2)

Si 100:O 80-120:C 90-150 (i.e. x=0.8 to 1.2, y=0.9 to 1.5)

Si 100:O 90-120:C 90-140 (i.e. x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100:O 92-107:C 116-133 (i.e. x=0.92 to 1.07, y=1.16 to 1.33).

The atomic ratio can be determined by XPS. Taking into account the Hatoms, which are not measured by XPS, the tie coating or layer 289 maythus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z) (or itsequivalent SiO_(x)C_(y)), for example where w is 1, x is from about 0.5to about 2.4, y is from about 0.6 to about 3, and z is from about 2 toabout 9. Typically, tie coating or layer 289 would hence contain 36% to41% carbon normalized to 100% carbon plus oxygen plus silicon.

Optionally, the tie coating or layer can be similar or identical incomposition with the pH protective coating or layer 286 describedelsewhere in this specification, although this is not a requirement.

Optionally, the tie coating or layer 289 is on average between 5 and 200nm (nanometers), optionally between 5 and 100 nm, optionally between 5and 20 nm thick. These thicknesses are not critical. Commonly but notnecessarily, the tie coating or layer 289 will be relatively thin, sinceits function is to change the surface properties of the substrate.

The tie coating or layer 289 has an interior surface facing the lumen212 and an outer surface facing the wall 214 interior surface.Optionally, the tie coating or layer 286 is at least coextensive withthe barrier coating or layer. Optionally, the tie coating or layer isapplied by PECVD, for example of a precursor feed comprisingoctamethylcyclotetrasiloxane (OMCTS), tetramethyldisiloxane (TMDSO), orhexamethyldisiloxane (HMDSO).

Barrier Coating or Layer

Referring to FIGS. 1 and 2, a barrier coating or layer 288 optionallycan be deposited by plasma enhanced chemical vapor deposition (PECVD) orother chemical vapor deposition processes on the vessel of apharmaceutical package, for example a thermoplastic package, to preventoxygen, carbon dioxide, or other gases from entering the vessel, thebarrier coating 288 optionally being effective to reduce the ingress ofatmospheric gas into the lumen 210 compared to an uncoated vessel 210,and/or to prevent leaching of the pharmaceutical material into orthrough the package wall.

The barrier coating or layer 286 optionally can be applied directly orindirectly to the thermoplastic wall 214 (for example the tie coating orlayer 289 can be interposed between them) so that in the filledpharmaceutical package or other vessel 210 the barrier coating or layer286 is located between the inner or interior surface of the wall 214 andthe lumen 212 that is adapted to contain a fluid to be stored. Thebarrier coating or layer 286 of SiO_(x) is supported by thethermoplastic wall 214. The barrier coating or layer 286 as describedelsewhere in this specification, or in U.S. Pat. No. 7,985,188, can beused in any embodiment.

The barrier layer optionally is characterized as an “SiO_(x)” coating,and contains silicon, oxygen, and optionally other elements, in which x,the ratio of oxygen to silicon atoms, is from about 1.5 to about 2.9, or1.5 to about 2.6, or about 2. One suitable barrier composition is onewhere x is 2.3, for example.

Optionally, the barrier coating or layer 288 is from 2 to 1000 nm thick,optionally from 4 nm to 500 nm thick, optionally between 10 and 200 nmthick, optionally from 20 to 200 nm thick, optionally from 20 to 30 nmthick, and comprises SiO_(x), wherein x is from 1.5 to 2.9. The barriercoating or layer 288 of SiO_(x) has an interior surface 220 facing thelumen 212 and an outer surface 222 facing the interior surface of thetie coating or layer 289. For example, the barrier coating or layer suchas 288 of any embodiment can be applied at a thickness of at least 2 nm,or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, orat least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700nm, or at least 800 nm, or at least 900 nm. The barrier coating or layercan be up to 1000 nm, or at most 900 nm, or at most 800 nm, or at most700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or atmost 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, orat most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, orat most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, orat most 5 nm thick.

Ranges of from 4 nm to 500 nm thick, optionally from 7 nm to 400 nmthick, optionally from 10 nm to 300 nm thick, optionally from 20 nm to200 nm thick, optionally from 20 to 30 nm thick, optionally from 30 nmto 100 nm thick are contemplated. Specific thickness ranges composed ofany one of the minimum thicknesses expressed above, plus any equal orgreater one of the maximum thicknesses expressed above, are expresslycontemplated.

The thickness of the SiO_(x) or other barrier coating or layer can bemeasured, for example, by transmission electron microscopy (TEM), andits composition can be measured by X-ray photoelectron spectroscopy(XPS).

Optionally, the barrier coating or layer 288 is effective to reduce theingress of atmospheric gas into the lumen compared to a vessel without abarrier coating or layer. Optionally, the barrier coating or layer 288provides a barrier to oxygen that has permeated the wall 214.Optionally, the barrier coating or layer 288 is a barrier to extractionof the composition of the wall 214 by the contents of the lumen 212.

pH Protective Coating or Layer

Certain barrier coatings or layers 286 such as SiO_(x) as defined herehave been found to have the characteristic of being subject to beingmeasurably diminished in barrier improvement factor in less than sixmonths as a result of attack by certain relatively high pH contents ofthe coated vessel as described elsewhere in this specification,particularly where the barrier coating or layer directly contacts thecontents. The inventors have found that barrier layers or coatings ofSiO_(x) are eroded or dissolved by some fluids, for example aqueouscompositions having a pH above about 5. Since coatings applied bychemical vapor deposition can be very thin—tens to hundreds ofnanometers thick—even a relatively slow rate of erosion can remove orreduce the effectiveness of the barrier layer in less time than thedesired shelf life of a product package. This is particularly a problemfor aqueous fluid pharmaceutical compositions, since many of them have apH of roughly 7, or more broadly in the range of 4 to 8, alternativelyfrom 5 to 9, similar to the pH of blood and other human or animalfluids. The higher the pH of the pharmaceutical preparation, the morequickly it erodes or dissolves the SiO_(x) coating. Optionally, thisproblem can be addressed by protecting the barrier coating or layer 288,or other pH sensitive material, with a pH protective coating or layer286.

The pH protective coating or layer 286 optionally provides protection ofthe underlying barrier coating or layer 288 against contents of thevessel 210 having a pH from 4 to 8, including where a surfactant ispresent. For a prefilled pharmaceutical package that is in contact withthe contents of the lumen 212 from the time it is manufactured to thetime it is used, the pH protective coating or layer 286 optionallyprevents or inhibits attack of the barrier coating or layer 288sufficiently to maintain an effective oxygen barrier over the intendedshelf life of the prefilled syringe. The rate of erosion, dissolution,or leaching (different names for related concepts) of the pH protectivecoating or layer 286, if directly contacted by a fluid, is less than therate of erosion of the barrier coating or layer 288, if directlycontacted by the fluid having a pH of from 5 to 9. The pH protectivecoating or layer 286 is effective to isolate a fluid 218 having a pHbetween 5 and 9 from the barrier coating or layer 288, at least forsufficient time to allow the barrier coating to act as a barrier duringthe shelf life of the pharmaceutical package or other vessel 210.

The inventors have further found that certain pH protective coatings orlayers of SiO_(x)C_(y) or SiN_(x)C_(y) formed from polysiloxaneprecursors, which pH protective coatings or layers have a substantialorganic component, do not erode quickly when exposed to fluids, and infact erode or dissolve more slowly when the fluids have pHs within therange of 4 to 8 or 5 to 9. For example, at pH 8, the dissolution rate ofa pH protective coating or layer made from the precursoroctamethylcyclotetrasiloxane, or OMCTS, is quite slow. These pHprotective coatings or layers of SiO_(x)C_(y) or SiN_(x)C_(y) cantherefore be used to cover a barrier layer of SiO_(x), retaining thebenefits of the barrier layer by protecting it from the fluid in thepharmaceutical package. The protective layer is applied over at least aportion of the SiO_(x) layer to protect the SiO_(x) layer from contentsstored in a vessel, where the contents otherwise would be in contactwith the SiO_(x) layer.

Although the present invention does not depend upon the accuracy of thefollowing theory, it is further believed that effective pH protectivecoatings or layers for avoiding erosion can be made from siloxanes andsilazanes as described in this disclosure. SiO_(x)C_(y) or SiN_(x)C_(y)coatings deposited from cyclic siloxane or linear silazane precursors,for example octamethylcyclotetrasiloxane (OMCTS), are believed toinclude intact cyclic siloxane rings and longer series of repeatingunits of the precursor structure. These coatings are believed to benanoporous but structured and hydrophobic, and these properties arebelieved to contribute to their success as pH protective coatings orlayers, and also protective coatings or layers. This is shown, forexample, in U.S. Pat. No. 7,901,783. SiO_(x)C_(y) or SiN_(x)C_(y)coatings also can be deposited from linear siloxane or linear silazaneprecursors, for example hexamethyldisiloxane (HMDSO) ortetramethyldisiloxane (TMDSO).

The inventors offer the following theory of operation of the pHprotective coating or layer described here. The invention is not limitedby the accuracy of this theory or to the embodiments predictable by useof this theory.

The dissolution rate of the SiO_(x) barrier layer is believed to bedependent on SiO_(x) bonding within the layer. Oxygen bonding sites(silanols) are believed to increase the dissolution rate.

It is believed that the OMCTS-based pH protective coating or layer bondswith the silanol sites on the SiO_(x) barrier layer to “heal” orpassivate the SiO_(x) surface and thus dramatically reduces thedissolution rate. In this hypothesis, the thickness of the OMCTS layeris not the primary means of protection—the primary means is passivationof the SiO_(x) surface. It is contemplated that a pH protective coatingor layer as described in this specification can be improved byincreasing the crosslink density of the pH protective coating or layer.

The pH protective coating or layer 286 optionally is effective to keepthe barrier coating or layer 288 at least substantially undissolved as aresult of attack by the fluid 218 for a period of at least six months.

The pH protective coating or layer optionally can prevent or reduce theprecipitation of a compound or component of a composition in contactwith the pH protective coating or layer, in particular can prevent orreduce insulin precipitation or blood clotting, in comparison to theuncoated surface and/or to a barrier coated surface using HMDSO asprecursor.

Referring to FIGS. 1 and 2, the pH protective coating or layer 286 canbe composed of, comprise, or consist essentially ofSi_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)) orSi_(w)N_(X)C_(y)H_(z) or its equivalent SiN_(x)C_(y)), each as definedpreviously, preferably SiO_(x)C_(y), wherein x is from about 0.5 toabout 2.4 and y is from about 0.6 to about 3. The atomic ratios of Si,O, and C in the pH protective coating or layer 286 optionally can be:

Si 100:O 50-150:C 90-200 (i.e. x=0.5 to 1.5, y=0.9 to 2);

Si 100:O 70-130:C 90-200 (i.e. x=0.7 to 1.3, y=0.9 to 2)

Si 100:O 80-120:C 90-150 (i.e. x=0.8 to 1.2, y=0.9 to 1.5)

Si 100:O 90-120:C 90-140 (i.e. x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100:O 92-107:C 116-133 (i.e. x=0.92 to 1.07, y=1.16 to 1.33) or

Si 100:O 80-130:C 90-150.

Alternatively, the pH protective coating or layer can have atomicconcentrations normalized to 100% carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS) of less than 50%carbon and more than 25% silicon. Alternatively, the atomicconcentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to35% oxygen. Alternatively, the atomic concentrations are from 30 to 40%carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, theatomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and22 to 26% oxygen.

Optionally, the atomic concentration of carbon in the pH protectivecoating or layer, normalized to 100% of carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS), can be greaterthan the atomic concentration of carbon in the atomic formula for theorganosilicon precursor. For example, embodiments are contemplated inwhich the atomic concentration of carbon increases by from 1 to 80atomic percent, alternatively from 10 to 70 atomic percent,alternatively from 20 to 60 atomic percent, alternatively from 30 to 50atomic percent, alternatively from 35 to 45 atomic percent,alternatively from 37 to 41 atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the pH protectivecoating or layer can be increased in comparison to the organosiliconprecursor, and/or the atomic ratio of oxygen to silicon can be decreasedin comparison to the organosilicon precursor.

Optionally, the pH protective coating or layer can have an atomicconcentration of silicon, normalized to 100% of carbon, oxygen, andsilicon, as determined by X-ray photoelectron spectroscopy (XPS), lessthan the atomic concentration of silicon in the atomic formula for thefeed gas. For example, embodiments are contemplated in which the atomicconcentration of silicon decreases by from 1 to 80 atomic percent,alternatively by from 10 to 70 atomic percent, alternatively by from 20to 60 atomic percent, alternatively by from 30 to 55 atomic percent,alternatively by from 40 to 50 atomic percent, alternatively by from 42to 46 atomic percent.

As another option, a pH protective coating or layer is contemplated inany embodiment that can be characterized by a sum formula wherein theatomic ratio C:O can be increased and/or the atomic ratio Si:O can bedecreased in comparison to the sum formula of the organosiliconprecursor.

The atomic ratio of Si:O:C or Si:N:C can be determined by XPS (X-rayphotoelectron spectroscopy). Taking into account the H atoms, the pHprotective coating or layer may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z), or its equivalent SiO_(x)C_(y), for example wherew is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about3, and z is from about 2 to about 9.

The thickness of the pH protective coating or layer as appliedoptionally is between 10 and 1000 nm; alternatively from 10 nm to 900nm; alternatively from 10 nm to 800 nm; alternatively from 10 nm to 700nm; alternatively from 10 nm to 600 nm; alternatively from 10 nm to 500nm; alternatively from 10 nm to 400 nm; alternatively from 10 nm to 300nm; alternatively from 10 nm to 200 nm; alternatively from 10 nm to 100nm; alternatively from 10 nm to 50 nm; alternatively from 20 nm to 1000nm; alternatively from 50 nm to 1000 nm; alternatively from 50 nm to 800nm; optionally from 50 to 500 nm; optionally from 100 to 200 nm;alternatively from 100 nm to 700 nm; alternatively from 100 nm to 200nm; alternatively from 300 to 600 nm. The thickness does not need to beuniform throughout the vessel, and will typically vary from thepreferred values in portions of a vessel.

The pH protective coating or layer can have a density between 1.25 and1.65 g/cm³, alternatively between 1.35 and 1.55 g/cm³, alternativelybetween 1.4 and 1.5 g/cm³, alternatively between 1.4 and 1.5 g/cm³,alternatively between 1.44 and 1.48 g/cm³, as determined by X-rayreflectivity (XRR). Optionally, the organosilicon compound can beoctamethylcyclotetrasiloxane and the pH protective coating or layer canhave a density which can be higher than the density of a pH protectivecoating or layer made from HMDSO as the organosilicon compound under thesame PECVD reaction conditions.

The pH protective coating or layer optionally can have an RMS surfaceroughness value (measured by AFM) of from about 5 to about 9, optionallyfrom about 6 to about 8, optionally from about 6.4 to about 7.8. TheR_(a) surface roughness value of the pH protective coating or layer,measured by AFM, can be from about 4 to about 6, optionally from about4.6 to about 5.8. The R_(max) surface roughness value of the pHprotective coating or layer, measured by AFM, can be from about 70 toabout 160, optionally from about 84 to about 142, optionally from about90 to about 130.

The interior surface of the pH protective optionally can have a contactangle (with distilled water) of from 90° to 110°, optionally from 80° to120°, optionally from 70° to 130°, as measured by Goniometer Anglemeasurement of a water droplet on the pH protective surface, per ASTMD7334-08 “Standard Practice for Surface Wettability of Coatings,Substrates and Pigments by Advancing Contact Angle Measurement,”

Optionally an FTIR absorbance spectrum of the pH protective coating orlayer 286 of any embodiment has a ratio greater than 0.75 between themaximum amplitude of the Si—O—Si symmetrical stretch peak normallylocated between about 1000 and 1040 cm-1, and the maximum amplitude ofthe Si—O—Si assymmetric stretch peak normally located between about 1060and about 1100 cm-1. Alternatively in any embodiment, this ratio can beat least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or atleast 1.2. Alternatively in any embodiment, this ratio can be at most1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. Anyminimum ratio stated here can be combined with any maximum ratio statedhere, as an alternative embodiment of the invention of FIGS. 1-5.

Optionally, in any embodiment the pH protective coating or layer 286, inthe absence of the medicament, has a non-oily appearance. Thisappearance has been observed in some instances to distinguish aneffective pH protective coating or layer from a lubricity layer, whichin some instances has been observed to have an oily (i.e. shiny)appearance.

Optionally, for the pH protective coating or layer 286 in anyembodiment, the silicon dissolution rate by a 50 mM potassium phosphatebuffer diluted in water for injection, adjusted to pH 8 withconcentrated nitric acid, and containing 0.2 wt. % polysorbate-80surfactant, (measured in the absence of the medicament, to avoidchanging the dissolution reagent), at 40° C., is less than 170 ppb/day.(Polysorbate-80 is a common ingredient of pharmaceutical preparations,available for example as Tween®-80 from Uniqema Americas LLC, WilmingtonDel.)

Optionally, for the pH protective coating or layer 286 in anyembodiment, the silicon dissolution rate is less than 160 ppb/day, orless than 140 ppb/day, or less than 120 ppb/day, or less than 100ppb/day, or less than 90 ppb/day, or less than 80 ppb/day. Optionally,in any embodiment of FIGS. 24-26 the silicon dissolution rate is morethan 10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, ormore than 40 ppb/day, or more than 50 ppb/day, or more than 60 ppb/day.Any minimum rate stated here can be combined with any maximum ratestated here for the pH protective coating or layer 286 in anyembodiment.

Optionally, for the pH protective coating or layer 286 in any embodimentthe total silicon content of the pH protective coating or layer andbarrier coating, upon dissolution into a test composition with a pH of 8from the vessel, is less than 66 ppm, or less than 60 ppm, or less than50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

The pH protective coating or layer 286 has an interior surface facingthe lumen 212 and an outer surface facing the interior surface of thebarrier coating or layer 288. Optionally, the pH protective coating orlayer 286 is at least coextensive with the barrier coating or layer 288.The pH protective coating or layer 286 alternatively can be lessextensive than the barrier coating, as when the fluid does not contactor seldom is in contact with certain parts of the barrier coating absentthe pH protective coating or layer. The pH protective coating or layer286 alternatively can be more extensive than the barrier coating, as itcan cover areas that are not provided with a barrier coating.

The pH protective coating or layer 286 optionally can be applied byplasma enhanced chemical vapor deposition (PECVD) of a precursor feedcomprising an acyclic siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclicsilazane, a polysilsesquiazane, a silatrane, a silquasilatrane, asilproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane,or a combination of any two or more of these precursors. Someparticular, non-limiting precursors contemplated for such use includeoctamethylcyclotetrasiloxane (OMCTS).

Optionally, an FTIR absorbance spectrum of the pH protective coating orlayer 286 has a ratio greater than 0.75 between the maximum amplitude ofthe Si—O—Si symmetrical stretch peak between about 1000 and 1040 cm⁻¹,and the maximum amplitude of the Si—O—Si assymmetric stretch peakbetween about 1060 and about 1100 cm⁻¹.

In the presence of a fluid composition having a pH between 5 and 9contained in the lumen 212, the calculated shelf life of the vessel 210is more than six months at a storage temperature of 4° C. Optionally,the rate of erosion of the pH protective coating or layer 286, ifdirectly contacted by a fluid composition having a pH of 8, is less than20% optionally less than 15%, optionally less than 10%, optionally lessthan 7%, optionally from 5% to 20%, optionally 5% to 15%, optionally 5%to 10%, optionally 5% to 7%, of the rate of erosion of the barriercoating or layer 288, if directly contacted by the same fluidcomposition under the same conditions. Optionally, the fluid compositionremoves the pH protective coating or layer 286 at a rate of 1 nm or lessof pH protective coating or layer thickness per 44 hours of contact withthe fluid composition.

Optionally, the silicon dissolution rate of the pH protective coating orlayer and barrier coating or layer by a 50 mM potassium phosphate bufferdiluted in water for injection, adjusted to pH 8 with concentratednitric acid, and containing 0.2 wt. % polysorbate-80 surfactant from thevessel is less than 170 parts per billion (ppb)/day.

Optionally, the total silicon content of the pH protective coating orlayer 286 and the barrier coating or layer 288, upon dissolution into0.1 N potassium hydroxide aqueous solution at 40° C. from the vessel, isless than 66 ppm.

Optionally, the calculated shelf life of the vessel 210 (total Si/Sidissolution rate) is more than 2 years.

Optionally, the pH protective coating or layer 286 shows an O-Parametermeasured with attenuated total reflection (ATR) of less than 0.4,measured as:

${O\text{-}{Parameter}} = \frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}^{- 1}}{{Maximum}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu}{from}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{{cm}^{- 1}.}}$

The O-Parameter is defined in U.S. Pat. No. 8,067,070, which claims anO-parameter value of most broadly from 0.4 to 0.9. It can be measuredfrom physical analysis of an FTIR amplitude versus wave number plot tofind the numerator and denominator of the above expression, as shown inFIG. 6, which is the same as FIG. 5 of U.S. Pat. No. 8,067,070, exceptannotated to show interpolation of the wave number and absorbance scalesto arrive at an absorbance at 1253 cm-1 of 0.0424 and a maximumabsorbance at 1000 to 1100 cm-1 of 0.08, resulting in a calculatedO-parameter of 0.53. The O-Parameter can also be measured from digitalwave number versus absorbance data.

U.S. Pat. No. 8,067,070 asserts that the claimed O-parameter rangeprovides a superior pH protective coating or layer, relying onexperiments only with HMDSO and HMDSN, which are both non-cyclicsiloxanes. Surprisingly, it has been found by the present inventors that0-parameters outside the ranges claimed in U.S. Pat. No. 8,067,070provide even better results than are obtained in U.S. Pat. No.8,067,070. Alternatively in the embodiment of FIGS. 1-5, the O-parameterhas a value of from 0.1 to 0.39, or from 0.15 to 0.37, or from 0.17 to0.35.

Optionally, the pH protective coating or layer shows an N-Parametermeasured with attenuated total reflection (ATR) of less than 0.7,measured as:

${N\text{-}{Parameter}} = \frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 840\mspace{14mu}{cm}^{- 1}}{{Intensity}\mspace{14mu}{at}\mspace{14mu} 799\mspace{14mu}{{cm}^{- 1}.}}$

The N-Parameter is also described in U.S. Pat. No. 8,067,070, and ismeasured analogously to the O-Parameter except that intensities at twospecific wave numbers are used—neither of these wave numbers is a range.U.S. Pat. No. 8,067,070 claims a passivation layer with an N-Parameterof 0.7 to 1.6. Again, the present inventors have made better coatingsemploying a pH protective coating or layer 286 having an N-Parameterlower than 0.7, as described above. Alternatively, the N-parameter has avalue of at least 0.3, or from 0.4 to 0.6, or at least 0.53.

The protective coating or layer of Si_(w)O_(x)C_(y) or its equivalentSiO_(x)C_(y) also can have utility as a hydrophobic layer, independentof whether it also functions as a pH protective coating or layer.Suitable hydrophobic coatings or layers and their application,properties, and use are described in U.S. Pat. No. 7,985,188. Dualfunctional protective/hydrophobic coatings or layers having theproperties of both types of coatings or layers can be provided for anyembodiment of the present invention.

Graded Composite Layer

Another expedient contemplated here, for adjacent layers of SiO_(x) anda pH protective coating or layer, is a graded composite of any two ormore adjacent PECVD layers, for example the barrier coating or layer 288and a pH protective coating or layer 286 and/or a lubricity coating orlayer 281. A graded composite can be separate layers of a protectiveand/or barrier layer or coating with a transition or interface ofintermediate composition between them, or separate layers of aprotective and/or hydrophobic layer and SiO_(x) with an intermediatedistinct pH protective coating or layer of intermediate compositionbetween them, or a single coating or layer that changes continuously orin steps from a composition of a protective and/or hydrophobic layer toa composition more like SiO_(x), going through the primer coating orlayer in a normal direction.

The grade in the graded composite can go in either direction. Forexample, the composition of SiO_(x) can be applied directly to thesubstrate and graduate to a composition further from the surface of aprimer coating or layer, and optionally can further graduate to anothertype of coating or layer, such as a hydrophobic coating or layer or alubricity coating or layer. Additionally, in any embodiment an adhesioncoating or layer, for example Si_(w)O_(x)C_(y), or its equivalentSiO_(x)C_(y), optionally can be applied directly to the substrate beforeapplying the barrier layer. A graduated primer coating or layer isparticularly contemplated if a layer of one composition is better foradhering to the substrate than another, in which case thebetter-adhering composition can, for example, be applied directly to thesubstrate. It is contemplated that the more distant portions of thegraded primer coating or layer can be less compatible with the substratethan the adjacent portions of the graded primer coating or layer, sinceat any point the primer coating or layer is changing gradually inproperties, so adjacent portions at nearly the same depth of the primercoating or layer have nearly identical composition, and more widelyphysically separated portions at substantially different depths can havemore diverse properties. It is also contemplated that a primer coatingor layer portion that forms a better barrier against transfer ofmaterial to or from the substrate can be directly against the substrate,to prevent the more remote primer coating or layer portion that forms apoorer barrier from being contaminated with the material intended to bebarred or impeded by the barrier.

The applied coatings or layers, instead of being graded, optionally canhave sharp transitions between one layer and the next, without asubstantial gradient of composition. Such primer coating or layer can bemade, for example, by providing the gases to produce a layer as a steadystate flow in a non-plasma state, then energizing the system with abrief plasma discharge to form a coating or layer on the substrate. If asubsequent primer coating or layer is to be applied, the gases for theprevious primer coating or layer are cleared out and the gases for thenext primer coating or layer are applied in a steady-state fashionbefore energizing the plasma and again forming a distinct layer on thesurface of the substrate or its outermost previous primer coating orlayer, with little if any gradual transition at the interface.

An embodiment can be carried out under conditions effective to form ahydrophobic pH protective coating or layer on the substrate. Optionally,the hydrophobic characteristics of the pH protective coating or layercan be set by setting the ratio of the O2 to the organosilicon precursorin the gaseous reactant, and/or by setting the electric power used forgenerating the plasma. Optionally, the pH protective coating or layercan have a lower wetting tension than the uncoated surface, optionally awetting tension of from 20 to 72 dyne/cm, optionally from 30 to 60dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm.Optionally, the pH protective coating or layer can be more hydrophobicthan the uncoated surface.

Equipment

PECVD Apparatus for Forming PECVD Coating or Layer

PECVD apparatus, a system and precursor materials suitable for applyingany of the PECVD coatings or layers described in this specification,specifically including the tie coating or layer 289, the barrier coatingor layer 288, or the pH protective coating or layer 286 is described indescribed in U.S. Pat. No. 7,985,188, which is incorporated byreference.

An overview of these conditions is provided in FIG. 32, which shows avessel processing system adapted for making such a vessel. The vesselshaving walls 214 can be conveyed to a tie coater 302, which is suitableapparatus for applying a tie coating or layer to the interior surface ofthe wall, such as the PECVD apparatus described in U.S. Pat. No.7,985,188.

The vessels can then be conveyed to a barrier coater 304, which issuitable apparatus for applying a barrier coating or layer to theinterior surface of the wall, such as the PECVD apparatus described inU.S. Pat. No. 7,985,188.

The vessels can then be conveyed to a pH protective coater 306, which issuitable apparatus for applying a pH protective coating or layer to theinterior surface of the wall, such as the PECVD apparatus described inU.S. Pat. No. 7,985,188. This then completes the coating set.

Optionally, further steps can be carried out by the system. For example,the coated vessels can be conveyed to a fluid filler 308 which placesfluid from a fluid supply 310 into the lumens of the coated vessels.

For another example the filled vessels can be conveyed to a closureinstaller 312, which takes closures, for example plungers or stoppers,from a closure supply 314 and seats them in the lumens of the coatedvessels.

In any embodiment of the invention, the tie coating or layer optionallycan be applied by plasma enhanced chemical vapor deposition (PECVD).

In any embodiment of the invention, the barrier coating or layeroptionally can be applied by PECVD.

In any embodiment of the invention, the pH protective coating or layeroptionally can be applied by PECVD.

In any embodiment of the invention, the vessel can comprise or consistof a syringe barrel, a vial, cartridge or a blister package.

Reaction conditions for forming the SiO_(x) barrier layer are describedin U.S. Pat. No. 7,985,188, which is incorporated by reference.

The tie or adhesion coating or layer can be produced, for example, usingas the precursor tetramethyldisiloxane (TMDSO) or hexamethyldisiloxane(HMDSO) at a flow rate of 0.5 to 10 sccm, preferably 1 to 5 sccm; oxygenflow of 0.25 to 5 sccm, preferably 0.5 to 2.5 sccm; and argon flow of 1to 120 sccm, preferably in the upper part of this range for a 1 mLsyringe and the lower part of this range for a 5 ml. vial. The overallpressure in the vessel during PECVD can be from 0.01 to 10 Torr,preferably from 0.1 to 1.5 Torr. The power level applied can be from 5to 100 Watts, preferably in the upper part of this range for a 1 mLsyringe and the lower part of this range for a 5 ml. vial. Thedeposition time (i.e. “on” time for RF power) is from 0.1 to 10 seconds,preferably 1 to 3 seconds. The power cycle optionally can be ramped orsteadily increased from 0 Watts to full power over a short time period,such as 2 seconds, when the power is turned on, which may improve theplasma uniformity. The ramp up of power over a period of time isoptional, however.

The pH protective coating or layer 286 coating or layer described inthis specification can be applied in many different ways. For oneexample, the low-pressure PECVD process described in U.S. Pat. No.7,985,188 can be used. For another example, instead of usinglow-pressure PECVD, atmospheric PECVD can be employed to deposit the pHprotective coating or layer. For another example, the coating can besimply evaporated and allowed to deposit on the SiO_(x) layer to beprotected. For another example, the coating can be sputtered on theSiO_(x) layer to be protected. For still another example, the pHprotective coating or layer 286 can be applied from a liquid medium usedto rinse or wash the SiO_(x) layer.

Other precursors and methods can be used to apply the pH protectivecoating or layer or passivating treatment. For example, hexamethylenedisilazane (HMDZ) can be used as the precursor. HMDZ has the advantageof containing no oxygen in its molecular structure. This passivationtreatment is contemplated to be a surface treatment of the SiO_(x)barrier layer with HMDZ. To slow down and/or eliminate the decompositionof the silicon dioxide coatings at silanol bonding sites, the coatingmust be passivated. It is contemplated that passivation of the surfacewith HMDZ (and optionally application of a few mono layers of theHMDZ-derived coating) will result in a toughening of the surface againstdissolution, resulting in reduced decomposition. It is contemplated thatHMDZ will react with the —OH sites that are present in the silicondioxide coating, resulting in the evolution of NH3 and bonding ofS—(CH3)3 to the silicon (it is contemplated that hydrogen atoms will beevolved and bond with nitrogen from the HMDZ to produce NH3).

It is contemplated that this HMDZ passivation can be accomplishedthrough several possible paths.

One contemplated path is dehydration/vaporization of the HMDZ at ambienttemperature. First, an SiO_(x) surface is deposited, for example usinghexamethylene disiloxane (HMDSO). The as-coated silicon dioxide surfaceis then reacted with HMDZ vapor. In an embodiment, as soon as theSiO_(x) surface is deposited onto the article of interest, the vacuum ismaintained. The HMDSO and oxygen are pumped away and a base vacuum isachieved. Once base vacuum is achieved, HMDZ vapor is flowed over thesurface of the silicon dioxide (as coated on the part of interest) atpressures from the mTorr range to many Torr. The HMDZ is then pumpedaway (with the resulting NH3 that is a byproduct of the reaction). Theamount of NH3 in the gas stream can be monitored (with a residual gasanalyzer—RGA—as an example) and when there is no more NH3 detected, thereaction is complete. The part is then vented to atmosphere (with aclean dry gas or nitrogen). The resulting surface is then found to havebeen passivated. It is contemplated that this method optionally can beaccomplished without forming a plasma.

Alternatively, after formation of the SiO_(x) barrier coating or layer,the vacuum can be broken before dehydration/vaporization of the HMDZ.Dehydration/vaporization of the HMDZ can then be carried out in eitherthe same apparatus used for formation of the SiO_(x) barrier coating orlayer or different apparatus.

Dehydration/vaporization of HMDZ at an elevated temperature is alsocontemplated. The above process can alternatively be carried out at anelevated temperature exceeding room temperature up to about 150° C. Themaximum temperature is determined by the material from which the coatedpart is constructed. An upper temperature should be selected that willnot distort or otherwise damage the part being coated.

Dehydration/vaporization of HMDZ with a plasma assist is alsocontemplated. After carrying out any of the above embodiments ofdehydration/vaporization, once the HMDZ vapor is admitted into the part,a plasma is generated. The plasma power can range from a few watts to100+ watts (similar powers as used to deposit the SiO_(x)). The above isnot limited to HMDZ and could be applicable to any molecule that willreact with hydrogen, for example any of the nitrogen-containingprecursors described in this specification.

Another way of applying the pH protective coating or layer is to applyas the pH protective coating or layer an amorphous carbon orfluorocarbon coating, or a combination of the two.

Amorphous carbon coatings can be formed by PECVD using a saturatedhydrocarbon, (e.g. methane or propane) or an unsaturated hydrocarbon(e.g. ethylene, acetylene) as a precursor for plasma polymerization.Fluorocarbon coatings can be derived from fluorocarbons (for example,hexafluoroethylene or tetrafluoroethylene). Either type of coating, or acombination of both, can be deposited by vacuum PECVD or atmosphericpressure PECVD. It is contemplated that that an amorphous carbon and/orfluorocarbon coating will provide better passivation of an SiO_(x)barrier layer than a siloxane coating since an amorphous carbon and/orfluorocarbon coating will not contain silanol bonds.

It is further contemplated that fluorosilicon precursors can be used toprovide a pH protective coating or layer over an SiO_(x) barrier layer.This can be carried out by using as a precursor a fluorinated silaneprecursor such as hexafluorosilane and a PECVD process. The resultingcoating would also be expected to be a non-wetting coating.

It is further contemplated that any embodiment of the pH protectivecoating or layer processes described in this specification can also becarried out without using the article to be coated to contain theplasma. For example, external surfaces of medical articles, for examplecatheters, surgical instruments, closures, and others can be protectedor passivated by sputtering the coating, employing a radio frequencytarget.

Yet another coating modality contemplated for protecting or passivatingan SiO_(x) barrier layer is coating the barrier layer using apolyamidoamine epichlorohydrin resin. For example, the barrier coatedpart can be dip coated in a fluid polyamidoamine epichlorohydrin resinmelt, solution or dispersion and cured by autoclaving or other heatingat a temperature between 60 and 100° C. It is contemplated that acoating of polyamidoamine epichlorohydrin resin can be preferentiallyused in aqueous environments between pH 5-8, as such resins are known toprovide high wet strength in paper in that pH range. Wet strength is theability to maintain mechanical strength of paper subjected to completewater soaking for extended periods of time, so it is contemplated that acoating of polyamidoamine epichlorohydrin resinon an SiO_(x) barrierlayer will have similar resistance to dissolution in aqueous media. Itis also contemplated that, because polyamidoamine epichlorohydrin resinimparts a lubricity improvement to paper, it will also provide lubricityin the form of a coating on a thermoplastic surface made of, forexample, COC or COP.

Even another approach for protecting an SiO_(x) layer is to apply as apH protective coating or layer a liquid-applied coating of apolyfluoroalkyl ether, followed by atmospheric plasma curing the pHprotective coating or layer. For example, it is contemplated that theprocess practiced under the trademark TriboGlide®, described in thisspecification, can be used to provide a pH protective coating or layerthat is also a lubricity layer, as TriboGlide® is conventionally used toprovide lubricity.

Exemplary PECVD reaction conditions for preparing a pH protectivecoating or layer 286 in a 3 ml sample size syringe with a ⅛″ diametertube (open at the end) are as follows:

For depositing a pH protective coating or layer, a precursor feed orprocess gas can be employed having a standard volume ratio of, forexample:

-   -   from 0.5 to 10 standard volumes, optionally from 1 to 6 standard        volumes, optionally from 2 to 4 standard volumes, optionally        equal to or less than 6 standard volumes, optionally equal to or        less than 2.5 standard volumes, optionally equal to or less than        1.5 standard volumes, optionally equal to or less than 1.25        standard volumes of the precursor, for example OMCTS or one of        the other precursors of any embodiment;    -   from 0 to 100 standard volumes, optionally from 1 to 200        standard volumes, optionally from 1 to 80 standard volumes,        optionally from 5 to 100 standard volumes, optionally from 10 to        70 standard volumes, of a carrier gas of any embodiment, for        example argon.    -   from 0.1 to 10 standard volumes, optionally from 0.1 to 2        standard volumes, optionally from 0.2 to 1.5 standard volumes,        optionally from 0.2 to 1 standard volumes, optionally from 0.5        to 1.5 standard volumes, optionally from 0.8 to 1.2 standard        volumes of an oxidizing agent.        The power level can be, for example, from 0.1-500 watts.        Specific Flow rates and power levels contemplated include:        OMCTS: 2.0 sccm        Oxygen: 0.7 sccm        Argon: 7.0 sccm        Power: 3.5 watts        PECVD Process for Trilayer Coating

Other general coating parameter ranges, with preferred ranges inparentheses, for a trilayer coating for a 1 mL syringe barrel are shownin the PECVD Trilayer Process General Parameters Tables (1 mL syringeand 5 mL vial).

PECVD Trilayer Process General Parameters Table (1 mL syringe) ParameterUnits Tie Barrier pH Protective Power W 40-90 140 40-90 (60-80) (60-80)TMDSO Flow sccm  1-10 None  1-10 (3-5) (3-5) HMDSO Flow sccm None 1.56None O₂ Flow sccm 0.5-5   20 0.5-5   (1.5-2.5) (1.5-2.5) Argon Flow sccm 40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None None NoneDeposition seconds 0.1-10  20 0.1-40  Time (1-3) (15-25) Tube PressureTorr 0.01-10   0.59 0.01-10   (0.1-1.5) (0.1-1.5)

PECVD Trilayer Process General Parameters Table (5 mL vial) ParameterUnits Adhesion Barrier Protection Power W 40-90 140 40-90 (60-80)(60-80) TMDSO Flow sccm  1-10 None  1-10 (3-5) (3-5) HMDSO Flow sccmNone 1.56 None O₂ Flow sccm 0.5-5   20 0.5-5   (1.5-2.5) (1.5-2.5) ArgonFlow sccm  40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None NoneNone Deposition Time seconds 0.1-10  20 0.1-40  (1-3) (15-25) TubePressure Torr 0.01-10   0.59 0.01-10   (0.1-1.5) (0.1-1.5)

Examples of specific coating parameters that have been used for a 1 mLsyringe and 5 mL vial are shown in the PECVD Trilayer Process SpecificParameters Tables (1 mL syringe and 5 mL vial):

PECVD Trilayer Process Specific Parameters Table (1 mL syringe)Parameter Units Tie Barrier Protection Power W 70 140 70 TMDSO Flow sccm4 None 4 HMDSO Flow sccm None 1.56 None O₂ Flow sccm 2 20 2 Argon Flowsccm 80 0 80 Ramp Time seconds None None None Deposition Time seconds2.5 20 10 Tube Pressure Torr 1 0.59 1

PECVD Trilayer Process Specific Parameters Table (5 mL vial) ParameterUnits Adhesion Barrier Protection Power W 20 40 20 TMDSO sccm 2 0 2 FlowHMDSO sccm 0 3 0 Flow O₂ Flow sccm 1 50 1 Argon Flow sccm 20 0 20 RampTime seconds 0 2 2 Deposition seconds 2.5 10 10 Time Tube Torr 0.85 1.290.85 Pressure

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 1 mL syringe as described above are 0.34 and 0.55,respectively.

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 5 mL vial are 0.24 and 0.63, respectively.

Vessels Generally

A vessel with a primer coating or layer as described herein and/orprepared according to a method described herein can be used forreception and/or storage and/or delivery of a compound or composition.The compound or composition can be sensitive, for example air-sensitive,oxygen-sensitive, sensitive to humidity and/or sensitive to mechanicalinfluences. It can be a biologically active compound or composition, forexample a pharmaceutical preparation or medicament like insulin or acomposition comprising insulin. In another aspect, it can be abiological fluid, optionally a bodily fluid, for example blood or ablood fraction. In certain aspects of the present invention, thecompound or composition can be a product to be administrated to asubject in need thereof, for example a product to be injected, likeblood (as in transfusion of blood from a donor to a recipient orreintroduction of blood from a patient back to the patient) or insulin.

A vessel with a primer coating or layer as described herein and/orprepared according to a method described herein can further be used forprotecting a compound or composition contained in its interior spaceagainst mechanical and/or chemical effects of the surface of the vesselmaterial. For example, it can be used for preventing or reducingprecipitation and/or clotting or platelet activation of the compound ora component of the composition, for example insulin precipitation orblood clotting or platelet activation.

It can further be used for protecting a compound or compositioncontained in its interior against the environment outside of thepharmaceutical package or other vessel, for example by preventing orreducing the entry of one or more compounds from the environmentsurrounding the vessel into the interior space of the vessel. Suchenvironmental compound can be a gas or liquid, for example anatmospheric gas or liquid containing oxygen, air, and/or water vapor.

A vessel with a primer coating or layer as described herein can also beevacuated and stored in an evacuated state. For example, the primercoating or layer allows better maintenance of the vacuum in comparisonto a corresponding vessel without a primer coating or layer. In oneaspect of this embodiment, the vessel with a primer coating or layer isa blood collection tube. The tube can also contain an agent forpreventing blood clotting or platelet activation, for example EDTA orheparin.

Any of the above-described embodiments can be made, for example, byproviding as the vessel a length of tubing from about 1 cm to about 200cm, optionally from about 1 cm to about 150 cm, optionally from about 1cm to about 120 cm, optionally from about 1 cm to about 100 cm,optionally from about 1 cm to about 80 cm, optionally from about 1 cm toabout 60 cm, optionally from about 1 cm to about 40 cm, optionally fromabout 1 cm to about 30 cm long, and processing it with a probe electrodeas described below. Particularly for the longer lengths in the aboveranges, it is contemplated that relative motion between the probe andthe vessel can be useful during primer coating or layer formation. Thiscan be done, for example, by moving the vessel with respect to the probeor moving the probe with respect to the vessel.

In these embodiments, it is contemplated that the barrier coating orlayer can be thinner or less complete than would be preferred to providethe high gas barrier integrity needed in an evacuated blood collectiontube. In these embodiments, it is contemplated that the primer coatingor layer can be thinner or less complete than would be preferred toprovide the long shelf life needed to store a liquid material in contactwith the barrier layer for an extended period.

As an optional feature of any of the foregoing embodiments the vesselhas a central axis.

As an optional feature of any of the foregoing embodiments the vesselwall is sufficiently flexible to be flexed at least once at 20° C.,without breaking the wall, over a range from at least substantiallystraight to a bending radius at the central axis of not more than 100times as great as the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the bendingradius at the central axis is not more than 90 times as great as, or notmore than 80 times as great as, or not more than 70 times as great as,or not more than 60 times as great as, or not more than 50 times asgreat as, or not more than 40 times as great as, or not more than 30times as great as, or not more than 20 times as great as, or not morethan 10 times as great as, or not more than 9 times as great as, or notmore than 8 times as great as, or not more than 7 times as great as, ornot more than 6 times as great as, or not more than 5 times as great as,or not more than 4 times as great as, or not more than 3 times as greatas, or not more than 2 times as great as, or not more than, the outerdiameter of the vessel.

As an optional feature of any of the foregoing embodiments the vesselwall can be a fluid-contacting surface made of flexible material.

As an optional feature of any of the foregoing embodiments the vessellumen can be the fluid flow passage of a pump.

As an optional feature of any of the foregoing embodiments the vesselcan be a blood bag adapted to maintain blood in good condition formedical use.

As an optional feature of any of the foregoing embodiments the polymericmaterial can be a silicone elastomer or a thermoplastic polyurethane, astwo examples, or any material suitable for contact with blood, or withinsulin.

In an optional embodiment, the vessel has an inner diameter of at least2 mm, or at least 4 mm.

As an optional feature of any of the foregoing embodiments the vessel isa tube.

As an optional feature of any of the foregoing embodiments the lumen hasat least two open ends.

Pharmaceutical Package

The vessel 210 illustrated most broadly by FIG. 1 and FIG. 2, isontemplated for use as a pharmaceutical package.

FIGS. 1-5 illustrate several exemplary pharmaceutical packages or othervessels 210 including a wall 214 enclosing a lumen 212, a fluid 218 inthe lumen 212, and a vessel coating or layer set 285 a barrier coatingor layer 288, and a pH protective coating or layer 286. The fluid 218 iscontained in the lumen 212. Optionally for any of the embodiments ofFIGS. 1-5, the fluid 218 is an aqueous fluid having a pH between 5 and6, optionally between 6 and 7, optionally between 7 and 8, optionallybetween 8 and 9, optionally between 6.5 and 7.5, optionally between 7.5and 8.5, optionally between 8.5 and 9. Optionally, the pH protectivecoating or layer 286 is effective to isolate a fluid 218 from thebarrier coating 288. Optionally, the rate of erosion of the pHprotective coating or layer 286, if directly contacted by an aqueousfluid 218 having a pH between 5 and 9, is less than the rate of erosionof the barrier coating 288, if directly contacted by an aqueous fluid218 having a pH between 5 and 9. Optionally for any of the embodimentsof FIGS. 1-5, the pharmaceutical package 210 can have a shelf life,after the pharmaceutical package 210 is assembled, of at least one year,alternatively at least two years.

Optionally for any of the embodiments of FIGS. 1-5, the shelf life ismeasured at 3° C., alternatively at 4° C. or higher, alternatively at20° C. or higher, alternatively at 23° C., alternatively at 40° C.

Optionally for any of the embodiments of FIGS. 1-5, the fluid 218 is aliquid at 20° C. and ambient pressure at sea level, which is defined asa pressure of 760 mm Hg.

Optionally for any of the embodiments of FIGS. 1-5, the fluid 218 is anaqueous liquid.

Optionally for any of the embodiments of FIGS. 1-5, the pH protectivecoating or layer 286 contacting the fluid 218 is between 10 and 1000 nmthick, optionally between 50 and 500 nm thick, optionally between 100and 400 nm thick, optionally between 150 and 300 nm thick two yearsafter the pharmaceutical package 210 is assembled.

Referring to FIG. 19, the syringe such as 252 optionally comprises aplunger 258 having a plunger tip inserted in the barrel 250 and a pushrod. The plunger 258 optionally is provided with a lubricity layer, atleast on its surface in contact with the barrel interior surface 264.The lubricity coating or layer on the plunger tip is in the rightposition to prevent “sticktion” during storage and to continue to lowerthe friction between the plunger tip and barrel when the plunger isadvanced, and if applied by CVD is contemplated to be less subject todisplacement by the force exerted by the plunger tip on the barrel thantraditional silicon oil coatings or layers and more uniformly applied asa uniform coating rather than as isolated droplets of liquid.

Optionally, a hydrophilic further primer layer of SiO_(x) can be appliedon top of the primer coating or layer 286 made of SiO_(x)C_(y) orSiN_(x)C_(y). Although the portions of this further primer layer exposedto the fluid 218 will erode, if the pH is high enough, the portions ofthis further primer layer protected by the plunger seal(s) from thefluid 218 will remain in place and further reduce the Fi experiencedwhen the syringe is used.

Optionally for any of the embodiments of FIGS. 1-5, the pH of the fluid218 is between 5 and 6 and the thickness by TEM of the pH protectivecoating or layer 286 is at least 80 nm at the end of the shelf life.Alternatively, the pH of the fluid 218 is between 6 and 7 and thethickness by TEM of the pH protective coating or layer 286 is at least80 nm at the end of the shelf life. Alternatively, the pH of the fluid218 is between 7 and 8 and the thickness by TEM of the pH protectivecoating or layer 286 is at least 80 nm at the end of the shelf life.Alternatively, the pH of the fluid 218 is between 8 and 9 and thethickness by TEM of the pH protective coating or layer 286 is at least80 nm at the end of the shelf life. Alternatively, the pH of the fluid218 is between 5 and 6 and the thickness by TEM of the pH protectivecoating or layer 286 is at least 150 nm at the end of the shelf life.Alternatively, the pH of the fluid 218 is between 6 and 7 and thethickness by TEM of the pH protective coating or layer 286 is at least150 nm at the end of the shelf life. Alternatively, the pH of the fluid218 is between 7 and 8 and the thickness by TEM of the pH protectivecoating or layer 286 is at least 150 nm at the end of the shelf life.Alternatively, the pH of the fluid 218 is between 8 and 9 and thethickness by TEM of the pH protective coating or layer 286 is at least150 nm at the end of the shelf life.

Optionally for any of the embodiments of FIGS. 1-5, the fluid 218removes the pH protective coating or layer 286 at a rate of 1 nm or lessof pH protective coating or layer thickness per 44 hours of contact withthe fluid 218 (200 nm per year), alternatively 1 nm or less of pHprotective coating or layer thickness per 88 hours of contact with thefluid 218 (100 nm per year), alternatively 1 nm or less of pH protectivecoating or layer thickness per 175 hours of contact with the fluid 218(50 nm per year), alternatively 1 nm or less of pH protective coating orlayer thickness per 250 hours of contact with the fluid 218 (35 nm peryear), alternatively 1 nm or less of pH protective coating or layerthickness per 350 hours of contact with the fluid 218 (25 nm per year).The rate of removing the pH protective coating or layer can bedetermined by TEM from samples exposed to the fluid for known periods.

Optionally, in any embodiment of FIGS. 24-26 the calculated shelf lifeof the package (total Si/Si dissolution rate) is more than six months,or more than 1 year, or more than 18 months, or more than 2 years, ormore than 2½ years, or more than 3 years, or more than 4 years, or morethan 5 years, or more than 10 years, or more than 20 years. Optionally,in any embodiment of FIGS. 24-26 the calculated shelf life of thepackage (total Si/Si dissolution rate) is less than 60 years.

Any minimum time stated here can be combined with any maximum timestated here, as an alternative embodiment of the invention of FIGS. 1-5.

Optionally for any of the embodiments of FIGS. 1-5, the fluid 218comprises a member or a combination of two or more members selected fromany of the materials recited below. As several examples, the fluid 218can be a material selected from the group consisting of inhalationanesthetics, injectable drugs, liquid drugs (non-injectable), drugs in avariety of classes, and diagnostic tests.

Examples of suitable inhalation anesthetics to be contained in the lumen212 of FIGS. 1 and 2 include: Aliflurane; Chloroform; Cyclopropane;Desflurane (Suprane); Diethyl Ether; Enflurane (Ethrane); EthylChloride; Ethylene; Halothane (Fluothane); Isoflurane (Forane, Isoflo);Isopropenyl vinyl ether; Methoxyflurane; methoxyflurane; Methoxypropane;Nitrous Oxide; Roflurane; Sevoflurane (Sevorane, Ultane, Sevoflo);Teflurane; Trichloroethylene; Vinyl Ether; Xenon.

Examples of suitable injectable drugs to be contained in the lumen 212of FIGS. 1 and 2 include: Ablavar (Gadofosveset Trisodium Injection);Abarelix Depot; Abobotulinumtoxin A Injection (Dysport); ABT-263;ABT-869; ABX-EFG; Accretropin (Somatropin Injection); Acetadote(Acetylcysteine Injection); Acetazolamide Injection (AcetazolamideInjection); Acetylcysteine Injection (Acetadote); Actemra (TocilizumabInjection); Acthrel (Corticorelin Ovine Triflutate for Injection);Actummune; Activase; Acyclovir for Injection (Zovirax Injection);Adacel; Adalimumab; Adenoscan (Adenosine Injection); Adenosine Injection(Adenoscan); Adrenaclick; AdreView (lobenguane 1 123 Injection forIntravenous Use); Afluria; Ak-Fluor (Fluorescein Injection); Aldurazyme(Laronidase); Alglucerase Injection (Ceredase); Alkeran Injection(Melphalan Hcl Injection); Allopurinol Sodium for Injection (Aloprim);Aloprim (Allopurinol Sodium for Injection); Alprostadil; Alsuma(Sumatriptan Injection); ALTU-238; Amino Acid Injections; Aminosyn;Apidra; Apremilast; Alprostadil Dual Chamber System for Injection(Caverject Impulse); AMG 009; AMG 076; AMG 102; AMG 108; AMG 114; AMG162; AMG 220; AMG 221; AMG 222; AMG 223; AMG 317; AMG 379; AMG 386; AMG403; AMG 477; AMG 479; AMG 517; AMG 531; AMG 557; AMG 623; AMG 655; AMG706; AMG 714; AMG 745; AMG 785; AMG 811; AMG 827; AMG 837; AMG 853; AMG951; Amiodarone HCl Injection (Amiodarone HCl Injection); AmobarbitalSodium Injection (Amytal Sodium); Amytal Sodium (Amobarbital SodiumInjection); Anakinra; Anti-Abeta; Anti-Beta7; Anti-Beta20; Anti-CD4;Anti-CD20; Anti-CD40; Anti-IFNalpha; Anti-IL13; Anti-OX40L; Anti-oxLDS;Anti-NGF; Anti-NRP1; Arixtra; Amphadase (Hyaluronidase Inj); Ammonul(Sodium Phenylacetate and Sodium Benzoate Injection); Anaprox; AnzemetInjection (Dolasetron Mesylate Injection); Apidra (Insulin Glulisine[rDNA origin] Inj); Apomab; Aranesp (darbepoetin alfa); Argatroban(Argatroban Injection); Arginine Hydrochloride Injection (R-Gene 10);Aristocort; Aristospan; Arsenic Trioxide Injection (Trisenox); ArticaneHCl and Epinephrine Injection (Septocaine); Arzerra (OfatumumabInjection); Asclera (Polidocanol Injection); Ataluren; Ataluren-DMD;Atenolol Inj (Tenormin I.V. Injection); Atracurium Besylate Injection(Atracurium Besylate Injection); Avastin; Azactam Injection (AztreonamInjection); Azithromycin (Zithromax Injection); Aztreonam Injection(Azactam Injection); Baclofen Injection (Lioresal Intrathecal);Bacteriostatic Water (Bacteriostatic Water for Injection); BaclofenInjection (Lioresal Intrathecal); Bal in Oil Ampules (DimercarprolInjection); BayHepB; BayTet; Benadryl; Bendamustine HydrochlorideInjection (Treanda); Benztropine Mesylate Injection (Cogentin);Betamethasone Injectable Suspension (Celestone Soluspan); Bexxar;Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G ProcaineInjection); Blenoxane (Bleomycin Sulfate Injection); Bleomycin SulfateInjection (Blenoxane); Boniva Injection (Ibandronate Sodium Injection);Botox Cosmetic (OnabotulinumtoxinA for Injection); BR3-FC; Bravelle(Urofollitropin Injection); Bretylium (Bretylium Tosylate Injection);Brevital Sodium (Methohexital Sodium for Injection); Brethine;Briobacept; BTT-1023; Bupivacaine HCl; Byetta; Ca-DTPA (PentetateCalcium Trisodium Inj); Cabazitaxel Injection (Jevtana); CaffeineAlkaloid (Caffeine and Sodium Benzoate Injection); Calcijex Injection(Calcitrol); Calcitrol (Calcijex Injection); Calcium Chloride (CalciumChloride Injection 10%); Calcium Disodium Versenate (Edetate CalciumDisodium Injection); Campath (Altemtuzumab); Camptosar Injection(Irinotecan Hydrochloride); Canakinumab Injection (Ilaris); CapastatSulfate (Capreomycin for Injection); Capreomycin for Injection (CapastatSulfate); Cardiolite (Prep kit for Technetium Tc99 Sestamibi forInjection); Carticel; Cathflo; Cefazolin and Dextrose for Injection(Cefazolin Injection); Cefepime Hydrochloride; Cefotaxime; Ceftriaxone;Cerezyme; Carnitor Injection; Caverject; Celestone Soluspan; Celsior;Cerebyx (Fosphenytoin Sodium Injection); Ceredase (AlgluceraseInjection); Ceretec (Technetium Tc99m Exametazime Injection);Certolizumab; CF-101; Chloramphenicol Sodium Succinate (ChloramphenicolSodium Succinate Injection); Chloramphenicol Sodium Succinate Injection(Chloramphenicol Sodium Succinate); Cholestagel (Colesevelam HCL);Choriogonadotropin Alfa Injection (Ovidrel); Cimzia; Cisplatin(Cisplatin Injection); Clolar (Clofarabine Injection); ClomiphineCitrate; Clonidine Injection (Duraclon); Cogentin (Benztropine MesylateInjection); Colistimethate Injection (Coly-Mycin M); Coly-Mycin M(Colistimethate Injection); Compath; Conivaptan Hcl Injection(Vaprisol); Conjugated Estrogens for Injection (Premarin Injection);Copaxone; Corticorelin Ovine Triflutate for Injection (Acthrel); Corvert(Ibutilide Fumarate Injection); Cubicin (Daptomycin Injection); CF-101;Cyanokit (Hydroxocobalamin for Injection); Cytarabine Liposome Injection(DepoCyt); Cyanocobalamin; Cytovene (ganciclovir); D.H.E. 45;Dacetuzumab; Dacogen (Decitabine Injection); Dalteparin; Dantrium IV(Dantrolene Sodium for Injection); Dantrolene Sodium for Injection(Dantrium IV); Daptomycin Injection (Cubicin); Darbepoietin Alfa; DDAVPInjection (Desmopressin Acetate Injection); Decavax; DecitabineInjection (Dacogen); Dehydrated Alcohol (Dehydrated Alcohol Injection);Denosumab Injection (Prolia); Delatestryl; Delestrogen; DelteparinSodium; Depacon (Valproate Sodium Injection); Depo Medrol(Methylprednisolone Acetate Injectable Suspension); DepoCyt (CytarabineLiposome Injection); DepoDur (Morphine Sulfate XR Liposome Injection);Desmopressin Acetate Injection (DDAVP Injection); Depo-Estradiol;Depo-Provera 104 mg/ml; Depo-Provera 150 mg/ml; Depo-Testosterone;Dexrazoxane for Injection, Intravenous Infusion Only (Totect);Dextrose/Electrolytes; Dextrose and Sodium Chloride Inj (Dextrose 5% in0.9% Sodium Chloride); Dextrose; Diazepam Injection (DiazepamInjection); Digoxin Injection (Lanoxin Injection); Dilaudid-HP(Hydromorphone Hydrochloride Injection); Dimercarprol Injection (Bal inOil Ampules); Diphenhydramine Injection (Benadryl Injection);Dipyridamole Injection (Dipyridamole Injection); DMOAD; Docetaxel forInjection (Taxotere); Dolasetron Mesylate Injection (Anzemet Injection);Doribax (Doripenem for Injection); Doripenem for Injection (Doribax);Doxercalciferol Injection (Hectorol Injection); Doxil (Doxorubicin HclLiposome Injection); Doxorubicin Hcl Liposome Injection (Doxil);Duraclon (Clonidine Injection); Duramorph (Morphine Injection); Dysport(Abobotulinumtoxin A Injection); Ecallantide Injection (Kalbitor);EC-Naprosyn (naproxen); Edetate Calcium Disodium Injection (CalciumDisodium Versenate); Edex (Alprostadil for Injection); Engerix;Edrophonium Injection (Enlon); Eliglustat Tartate; Eloxatin (OxaliplatinInjection); Emend Injection (Fosaprepitant Dimeglumine Injection);Enalaprilat Injection (Enalaprilat Injection); Enlon (EdrophoniumInjection); Enoxaparin Sodium Injection (Lovenox); Eovist (GadoxetateDisodium Injection); Enbrel (etanercept); Enoxaparin; Epicel;Epinepherine; Epipen; Epipen Jr.; Epratuzumab; Erbitux; ErtapenemInjection (Invanz); Erythropoieten; Essential Amino Acid Injection(Nephramine); Estradiol Cypionate; Estradiol Valerate; Etanercept;Exenatide Injection (Byetta); Evlotra; Fabrazyme (Adalsidase beta);Famotidine Injection; FDG (Fludeoxyglucose F 18 Injection); Feraheme(Ferumoxytol Injection); Feridex I.V. (Ferumoxides Injectable Solution);Fertinex; Ferumoxides Injectable Solution (Feridex I.V.); FerumoxytolInjection (Feraheme); Flagyl Injection (Metronidazole Injection);Fluarix; Fludara (Fludarabine Phosphate); Fludeoxyglucose F 18 Injection(FDG); Fluorescein Injection (Ak-Fluor); Follistim AQ Cartridge(Follitropin Beta Injection); Follitropin Alfa Injection (Gonal-f RFF);Follitropin Beta Injection (Follistim AQ Cartridge); Folotyn(Pralatrexate Solution for Intravenous Injection); Fondaparinux; Forteo(Teriparatide (rDNA origin) Injection); Fostamatinib; FosaprepitantDimeglumine Injection (Emend Injection); Foscarnet Sodium Injection(Foscavir); Foscavir (Foscarnet Sodium Injection); Fosphenytoin SodiumInjection (Cerebyx); Fospropofol Disodium Injection (Lusedra); Fragmin;Fuzeon (enfuvirtide); GA101; Gadobenate Dimeglumine Injection(Multihance); Gadofosveset Trisodium Injection (Ablavar); GadoteridolInjection Solution (ProHance); Gadoversetamide Injection (OptiMARK);Gadoxetate Disodium Injection (Eovist); Ganirelix (Ganirelix AcetateInjection); Gardasil; GC1008; GDFD; Gemtuzumab Ozogamicin for Injection(Mylotarg); Genotropin; Gentamicin Injection; GENZ-112638; GolimumabInjection (Simponi Injection); Gonal-f RFF (Follitropin Alfa Injection);Granisetron Hydrochloride (Kytril Injection); Gentamicin Sulfate;Glatiramer Acetate; Glucagen; Glucagon; HAE1; Haldol (HaloperidolInjection); Havrix; Hectorol Injection (Doxercalciferol Injection);Hedgehog Pathway Inhibitor; Heparin; Herceptin; hG-CSF; Humalog; HumanGrowth Hormone; Humatrope; HuMax; Humegon; Humira; Humulin; IbandronateSodium Injection (Boniva Injection); Ibuprofen Lysine Injection(NeoProfen); Ibutilide Fumarate Injection (Corvert); Idamycin PFS(Idarubicin Hydrochloride Injection); Idarubicin Hydrochloride Injection(Idamycin PFS); Ilaris (Canakinumab Injection); Imipenem and Cilastatinfor Injection (Primaxin I.V.); Imitrex; Incobotulinumtoxin A forInjection (Xeomin); Increlex (Mecasermin [rDNA origin] Injection);Indocin IV (Indomethacin Inj); Indomethacin Inj (Indocin IV); Infanrix;Innohep; Insulin; Insulin Aspart [rDNA origin] Inj (NovoLog); InsulinGlargine [rDNA origin] Injection (Lantus); Insulin Glulisine [rDNAorigin] Inj (Apidra); Interferon alfa-2b, Recombinant for Injection(Intron A); Intron A (Interferon alfa-2b, Recombinant for Injection);Invanz (Ertapenem Injection); Invega Sustenna (Paliperidone PalmitateExtended-Release Injectable Suspension); Invirase (saquinavir mesylate);lobenguane 1123 Injection for Intravenous Use (AdreView); IopromideInjection (Ultravist); Ioversol Injection (Optiray Injection); Iplex(Mecasermin Rinfabate [rDNA origin] Injection); Iprivask; IrinotecanHydrochloride (Camptosar Injection); Iron Sucrose Injection (Venofer);Istodax (Romidepsin for Injection); Itraconazole Injection (SporanoxInjection); Jevtana (Cabazitaxel Injection); Jonexa; Kalbitor(Ecallantide Injection); KCL in D5NS (Potassium Chloride in 5% Dextroseand Sodium Chloride Injection); KCL in D5W; KCL in NS; Kenalog 10Injection (Triamcinolone Acetonide Injectable Suspension); Kepivance(Palifermin); Keppra Injection (Levetiracetam); Keratinocyte; KFG;Kinase Inhibitor; Kineret (Anakinra); Kinlytic (Urokinase Injection);Kinrix; Klonopin (clonazepam); Kytril Injection (GranisetronHydrochloride); lacosamide Tablet and Injection (Vimpat); LactatedRinger's; Lanoxin Injection (Digoxin Injection); Lansoprazole forInjection (Prevacid I.V.); Lantus; Leucovorin Calcium (LeucovorinCalcium Injection); Lente (L); Leptin; Levemir; Leukine Sargramostim;Leuprolide Acetate; Levothyroxine; Levetiracetam (Keppra Injection);Lovenox; Levocarnitine Injection (Carnitor Injection); Lexiscan(Regadenoson Injection); Lioresal Intrathecal (Baclofen Injection);Liraglutide [rDNA] Injection (Victoza); Lovenox (Enoxaparin SodiumInjection); Lucentis (Ranibizumab Injection); Lumizyme; Lupron(Leuprolide Acetate Injection); Lusedra (Fospropofol DisodiumInjection); Maci; Magnesium Sulfate (Magnesium Sulfate Injection);Mannitol Injection (Mannitol IV); Marcaine (Bupivacaine Hydrochlorideand Epinephrine Injection); Maxipime (Cefepime Hydrochloride forInjection); MDP Multidose Kit of Technetium Injection (Technetium Tc99mMedronate Injection); Mecasermin [rDNA origin] Injection (Increlex);Mecasermin Rinfabate [rDNA origin] Injection (Iplex); Melphalan HclInjection (Alkeran Injection); Methotrexate; Menactra; Menopur(Menotropins Injection); Menotropins for Injection (Repronex);Methohexital Sodium for Injection (Brevital Sodium); MethyldopateHydrochloride Injection, Solution (Methyldopate Hcl); Methylene Blue(Methylene Blue Injection); Methylprednisolone Acetate InjectableSuspension (Depo Medrol); MetMab; Metoclopramide Injection (ReglanInjection); Metrodin (Urofollitropin for Injection); MetronidazoleInjection (Flagyl Injection); Miacalcin; Midazolam (MidazolamInjection); Mimpara (Cinacalet); Minocin Injection (Minocycline Inj);Minocycline Inj (Minocin Injection); Mipomersen; Mitoxantrone forInjection Concentrate (Novantrone); Morphine Injection (Duramorph);Morphine Sulfate XR Liposome Injection (DepoDur); Morrhuate Sodium(Morrhuate Sodium Injection); Motesanib; Mozobil (Plerixafor Injection);Multihance (Gadobenate Dimeglumine Injection); Multiple Electrolytes andDextrose Injection; Multiple Electrolytes Injection; Mylotarg(Gemtuzumab Ozogamicin for Injection); Myozyme (Alglucosidase alfa);Nafcillin Injection (Nafcillin Sodium); Nafcillin Sodium (NafcillinInjection); Naltrexone XR Inj (Vivitrol); Naprosyn (naproxen); NeoProfen(Ibuprofen Lysine Injection); Nandrol Decanoate; NeostigmineMethylsulfate (Neostigmine Methylsulfate Injection); NEO-GAA; NeoTect(Technetium Tc 99m Depreotide Injection); Nephramine (Essential AminoAcid Injection); Neulasta (pegfilgrastim); Neupogen (Filgrastim);Novolin; Novolog; NeoRecormon; Neutrexin (Trimetrexate Glucuronate Inj);NPH (N); Nexterone (Amiodarone HCl Injection); Norditropin (SomatropinInjection); Normal Saline (Sodium Chloride Injection); Novantrone(Mitoxantrone for Injection Concentrate); Novolin 70/30 Innolet (70%NPH, Human Insulin Isophane Suspension and 30% Regular, Human InsulinInjection); NovoLog (Insulin Aspart [rDNA origin] Inj); Nplate(romiplostim); Nutropin (Somatropin (rDNA origin) for Inj); Nutropin AQ;Nutropin Depot (Somatropin (rDNA origin) for Inj); Octreotide AcetateInjection (Sandostatin LAR); Ocrelizumab; Ofatumumab Injection(Arzerra); Olanzapine Extended Release Injectable Suspension (ZyprexaRelprevv); Omnitarg; Omnitrope (Somatropin [rDNA origin] Injection);Ondansetron Hydrochloride Injection (Zofran Injection); OptiMARK(Gadoversetamide Injection); Optiray Injection (Ioversol Injection);Orencia; Osmitrol Injection in Aviva (Mannitol Injection in AvivaPlastic Vessel); Osmitrol Injection in Viaflex (Mannitol Injection inViaflex Plastic Vessel); Osteoprotegrin; Ovidrel (ChoriogonadotropinAlfa Injection); Oxacillin (Oxacillin for Injection); OxaliplatinInjection (Eloxatin); Oxytocin Injection (Pitocin); PaliperidonePalmitate Extended-Release Injectable Suspension (Invega Sustenna);Pamidronate Disodium Injection (Pamidronate Disodium Injection);Panitumumab Injection for Intravenous Use (Vectibix); PapaverineHydrochloride Injection (Papaverine Injection); Papaverine Injection(Papaverine Hydrochloride Injection); Parathyroid Hormone; ParicalcitolInjection Fliptop Vial (Zemplar Injection); PARP Inhibitor; Pediarix;PEGlntron; Peginterferon; Pegfilgrastim; Penicillin G Benzathine andPenicillin G Procaine; Pentetate Calcium Trisodium Inj (Ca-DTPA);Pentetate Zinc Trisodium Injection (Zn-DTPA); Pepcid Injection(Famotidine Injection); Pergonal; Pertuzumab; Phentolamine Mesylate(Phentolamine Mesylate for Injection); Physostigmine Salicylate(Physostigmine Salicylate (injection)); Physostigmine Salicylate(injection) (Physostigmine Salicylate); Piperacillin and TazobactamInjection (Zosyn); Pitocin (Oxytocin Injection); Plasma-Lyte 148(Multiple Electrolytes Inj); Plasma-Lyte 56 and Dextrose (MultipleElectrolytes and Dextrose Injection in Viaflex Plastic Vessel);PlasmaLyte; Plerixafor Injection (Mozobil); Polidocanol Injection(Asclera); Potassium Chloride; Pralatrexate Solution for IntravenousInjection (Folotyn); Pramlintide Acetate Injection (Symlin); PremarinInjection (Conjugated Estrogens for Injection); Prep kit for TechnetiumTc99 Sestamibi for Injection (Cardiolite); Prevacid I.V. (Lansoprazolefor Injection); Primaxin I.V. (Imipenem and Cilastatin for Injection);Prochymal; Procrit; Progesterone; ProHance (Gadoteridol InjectionSolution); Prolia (Denosumab Injection); Promethazine HCl Injection(Promethazine Hydrochloride Injection); Propranolol HydrochlorideInjection (Propranolol Hydrochloride Injection); Quinidine GluconateInjection (Quinidine Injection); Quinidine Injection (QuinidineGluconate Injection); R-Gene 10 (Arginine Hydrochloride Injection);Ranibizumab Injection (Lucentis); Ranitidine Hydrochloride Injection(Zantac Injection); Raptiva; Reclast (Zoledronic Acid Injection);Recombivarix HB; Regadenoson Injection (Lexiscan); Reglan Injection(Metoclopramide Injection); Remicade; Renagel; Renvela (SevelamerCarbonate); Repronex (Menotropins for Injection); Retrovir IV(Zidovudine Injection); rhApo2L/TRAIL; Ringer's and 5% DextroseInjection (Ringers in Dextrose); Ringer's Injection (Ringers Injection);Rituxan; Rituximab; Rocephin (ceftriaxone); Rocuronium Bromide Injection(Zemuron); Roferon-A (interferon alfa-2a); Romazicon (flumazenil);Romidepsin for Injection (Istodax); Saizen (Somatropin Injection);Sandostatin LAR (Octreotide Acetate Injection); Sclerostin Ab; Sensipar(cinacalcet); Sensorcaine (Bupivacaine HCl Injections); Septocaine(Articane HCl and Epinephrine Injection); Serostim LQ (Somatropin (rDNAorigin) Injection); Simponi Injection (Golimumab Injection); SodiumAcetate (Sodium Acetate Injection); Sodium Bicarbonate (SodiumBicarbonate 5% Injection); Sodium Lactate (Sodium Lactate Injection inAVIVA); Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul);Somatropin (rDNA origin) for Inj (Nutropin); Sporanox Injection(Itraconazole Injection); Stelara Injection (Ustekinumab); Stemgen;Sufenta (Sufentanil Citrate Injection); Sufentanil Citrate Injection(Sufenta); Sumavel; Sumatriptan Injection (Alsuma); Symlin; Symlin Pen;Systemic Hedgehog Antagonist; Synvisc-One (Hylan G-F 20 SingleIntra-articular Injection); Tarceva; Taxotere (Docetaxel for Injection);Technetium Tc 99m; Telavancin for Injection (Vibativ); TemsirolimusInjection (Torisel); Tenormin I.V. Injection (Atenolol Inj);Teriparatide (rDNA origin) Injection (Forteo); Testosterone Cypionate;Testosterone Enanthate; Testosterone Propionate; Tev-Tropin (Somatropin,rDNA Origin, for Injection); tgAAC94; Thallous Chloride; Theophylline;Thiotepa (Thiotepa Injection); Thymoglobulin (Anti-Thymocyte Globulin(Rabbit); Thyrogen (Thyrotropin Alfa for Injection); TicarcillinDisodium and Clavulanate Potassium Galaxy (Timentin Injection); TiganInjection (Trimethobenzamide Hydrochloride Injectable); TimentinInjection (Ticarcillin Disodium and Clavulanate Potassium Galaxy);TNKase; Tobramycin Injection (Tobramycin Injection); TocilizumabInjection (Actemra); Torisel (Temsirolimus Injection); Totect(Dexrazoxane for Injection, Intravenous Infusion Only); Trastuzumab-DM1;Travasol (Amino Acids (Injection)); Treanda (Bendamustine HydrochlorideInjection); Trelstar (Triptorelin Pamoate for Injectable Suspension);Triamcinolone Acetonide; Triamcinolone Diacetate; TriamcinoloneHexacetonide Injectable Suspension (Aristospan Injection 20 mg);Triesence (Triamcinolone Acetonide Injectable Suspension);Trimethobenzamide Hydrochloride Injectable (Tigan Injection);Trimetrexate Glucuronate Inj (Neutrexin); Triptorelin Pamoate forInjectable Suspension (Trelstar); Twinject; Trivaris (TriamcinoloneAcetonide Injectable Suspension); Trisenox (Arsenic Trioxide Injection);Twinrix; Typhoid Vi; Ultravist (Iopromide Injection); Urofollitropin forInjection (Metrodin); Urokinase Injection (Kinlytic); Ustekinumab(Stelara Injection); Ultralente (U); Valium (diazepam); Valproate SodiumInjection (Depacon); Valtropin (Somatropin Injection); VancomycinHydrochloride (Vancomycin Hydrochloride Injection); VancomycinHydrochloride Injection (Vancomycin Hydrochloride); Vaprisol (ConivaptanHcl Injection); VAQTA; Vasovist (Gadofosveset Trisodium Injection forIntravenous Use); Vectibix (Panitumumab Injection for Intravenous Use);Venofer (Iron Sucrose Injection); Verteporfin Inj (Visudyne); Vibativ(Telavancin for Injection); Victoza (Liraglutide [rDNA] Injection);Vimpat (lacosamide Tablet and Injection); Vinblastine Sulfate(Vinblastine Sulfate Injection); Vincasar PFS (Vincristine SulfateInjection); Victoza; Vincristine Sulfate (Vincristine SulfateInjection); Visudyne (Verteporfin Inj); Vitamin B-12; Vivitrol(Naltrexone XR Inj); Voluven (Hydroxyethyl Starch in Sodium ChlorideInjection); Xeloda; Xenical (orlistat); Xeomin (Incobotulinumtoxin A forInjection); Xolair; Zantac Injection (Ranitidine HydrochlorideInjection); Zemplar Injection (Paricalcitol Injection Fliptop Vial);Zemuron (Rocuronium Bromide Injection); Zenapax (daclizumab); Zevalin;Zidovudine Injection (Retrovir IV); Zithromax Injection (Azithromycin);Zn-DTPA (Pentetate Zinc Trisodium Injection); Zof ran Injection(Ondansetron Hydrochloride Injection); Zingo; Zoledronic Acid for Inj(Zometa); Zoledronic Acid Injection (Reclast); Zometa (Zoledronic Acidfor Inj); Zosyn (Piperacillin and Tazobactam Injection); ZyprexaRelprevv (Olanzapine Extended Release Injectable Suspension).

Examples of suitable liquid drugs (non-injectable) to be contained inthe lumen 212 of FIGS. 1 and 2 include: Abilify; AccuNeb (AlbuterolSulfate Inhalation Solution); Actidose Aqua (Activated CharcoalSuspension); Activated Charcoal Suspension (Actidose Aqua); Advair;Agenerase Oral Solution (Amprenavir Oral Solution); Akten (LidocaineHydrochloride Ophthalmic Gel); Alamast (Pemirolast Potassium OphthalmicSolution); Albumin (Human) 5% Solution (Buminate 5%); Albuterol SulfateInhalation Solution; Alinia; Alocril; Alphagan; Alrex; Alvesco;Amprenavir Oral Solution; Analpram-HC; Arformoterol Tartrate InhalationSolution (Brovana); Aristospan Injection 20 mg (TriamcinoloneHexacetonide Injectable Suspension); Asacol; Asmanex; Astepro; Astepro(Azelastine Hydrochloride Nasal Spray); Atrovent Nasal Spray(Ipratropium Bromide Nasal Spray); Atrovent Nasal Spray 0.06; AugmentinES-600; Azasite (Azithromycin Ophthalmic Solution); Azelaic Acid(Finacea Gel); Azelastine Hydrochloride Nasal Spray (Astepro); Azelex(Azelaic Acid Cream); Azopt (Brinzolamide Ophthalmic Suspension);Bacteriostatic Saline; Balanced Salt; Bepotastine; Bactroban Nasal;Bactroban; Beclovent; Benzac W; Betimol; Betoptic S; Bepreve;Bimatoprost Ophthalmic Solution; Bleph 10 (Sulfacetamide SodiumOphthalmic Solution 10%); Brinzolamide Ophthalmic Suspension (Azopt);Bromfenac Ophthalmic Solution (Xibrom); Bromhist; Brovana (ArformoterolTartrate Inhalation Solution); Budesonide Inhalation Suspension(Pulmicort Respules); Cambia (Diclofenac Potassium for Oral Solution);Capex; Carac; Carboxine-PSE; Carnitor; Cayston (Aztreonam for InhalationSolution); Cellcept; Centany; Cerumenex; Ciloxan Ophthalmic Solution(Ciprofloxacin HCL Ophthalmic Solution); Ciprodex; Ciprofloxacin HCLOphthalmic Solution (Ciloxan Ophthalmic Solution); Clemastine FumarateSyrup (Clemastine Fumarate Syrup); CoLyte (PEG Electrolytes Solution);Combiven; Comtan; Condylox; Cordran; Cortisporin Ophthalmic Suspension;Cortisporin Otic Suspension; Cromolyn Sodium Inhalation Solution (IntalNebulizer Solution); Cromolyn Sodium Ophthalmic Solution (Opticrom);Crystalline Amino Acid Solution with Electrolytes (AminosynElectrolytes); Cutivate; Cuvposa (Glycopyrrolate Oral Solution);Cyanocobalamin (CaloMist Nasal Spray); Cyclosporine Oral Solution(Gengraf Oral Solution); Cyclogyl; Cysview (HexaminolevulinateHydrochloride Intravesical Solution); DermOtic Oil (FluocinoloneAcetonide Oil Ear Drops); Desmopressin Acetate Nasal Spray; DDAVP;Derma-Smoothe/FS; Dexamethasone Intensol; Dianeal Low Calcium; DianealPD; Diclofenac Potassium for Oral Solution (Cambia); DidanosinePediatric Powder for Oral Solution (Videx); Differin; Dilantin 125(Phenytoin Oral Suspension); Ditropan; Dorzolamide HydrochlorideOphthalmic Solution (Trusopt); Dorzolamide Hydrochloride-Timolol MaleateOphthalmic Solution (Cosopt); Dovonex Scalp (Calcipotriene Solution);Doxycycline Calcium Oral Suspension (Vibramycin Oral); Efudex; Elaprase(Idursulfase Solution); Elestat (Epinastine HCl Ophthalmic Solution);Elocon; Epinastine HCl Ophthalmic Solution (Elestat); Epivir HBV; Epogen(Epoetin alfa); Erythromycin Topical Solution 1.5% (Staticin); Ethiodol(Ethiodized Oil); Ethosuximide Oral Solution (Zarontin Oral Solution);Eurax; Extraneal (Icodextrin Peritoneal Dialysis Solution); Felbatol;Feridex I.V. (Ferumoxides Injectable Solution); Flovent; Floxin Otic(Ofloxacin Otic Solution); Flo-Pred (Prednisolone Acetate OralSuspension); Fluoroplex; Flunisolide Nasal Solution (Flunisolide NasalSpray 0.025%); Fluorometholone Ophthalmic Suspension (FML); FlurbiprofenSodium Ophthalmic Solution (Ocufen); FML; Foradil; Formoterol FumarateInhalation Solution (Perforomist); Fosamax; Furadantin (NitrofurantoinOral Suspension); Furoxone; Gammagard Liquid (Immune GlobulinIntravenous (Human) 10%); Gantrisin (Acetyl Sulfisoxazole PediatricSuspension); Gatifloxacin Ophthalmic Solution (Zymar); Gengraf OralSolution (Cyclosporine Oral Solution); Glycopyrrolate Oral Solution(Cuvposa); Halcinonide Topical Solution (Halog Solution); Halog Solution(Halcinonide Topical Solution); HEP-LOCK U/P (Preservative-Free HeparinLock Flush Solution); Heparin Lock Flush Solution (Hepflush 10);Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview);Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab Elixir);Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution); IAPAntagonist; Isopto; Ipratropium Bromide Nasal Spray (Atrovent NasalSpray); Itraconazole Oral Solution (Sporanox Oral Solution); KetorolacTromethamine Ophthalmic Solution (Acular LS); Kaletra; Lanoxin; Lexiva;Leuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg);Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon);Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor);Levofloxacin Ophthalmic Solution 0.5% (Quixin); Lidocaine HCl SterileSolution (Xylocaine MPF Sterile Solution); Lok Pak (Heparin Lock FlushSolution); Lorazepam Intensol; Lortab Elixir (Hydrocodone Bitartrate andAcetaminophen Oral Solution); Lotemax (Loteprednol Etabonate OphthalmicSuspension); Loteprednol Etabonate Ophthalmic Suspension (Alrex); LowCalcium Peritoneal Dialysis Solutions (Dianeal Low Calcium); Lumigan(Bimatoprost Ophthalmic Solution 0.03% for Glaucoma); Lupron Depot 11.25mg (Leuprolide Acetate for Depot Suspension); Megestrol Acetate OralSuspension (Megestrol Acetate Oral Suspension); MEK Inhibitor; Mepron;Mesnex; Mestinon; Mesalamine Rectal Suspension Enema (Rowasa); Melquin-3Topical Solution (Hydroquinone 3% Topical Solution); MetMab;Methyldopate Hcl (Methyldopate Hydrochloride Injection, Solution);Methylin Oral Solution (Methylphenidate HCl Oral Solution 5 mg/5 mL and10 mg/5 mL); Methylprednisolone Acetate Injectable Suspension (DepoMedrol); Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL(Methylin Oral Solution); Methylprednisolone sodium succinate (SoluMedrol); Metipranolol Ophthalmic Solution (Optipranolol); Migranal;Miochol-E (Acetylcholine Chloride Intraocular Solution); Micro-K forLiquid Suspension (Potassium Chloride Extended Release Formulation forLiquid Suspension); Minocin (Minocycline Hydrochloride Oral Suspension);Nasacort; Neomycin and Polymyxin B Sulfates and Hydrocortisone;Nepafenac Ophthalmic Suspension (Nevanac); Nevanac (Nepafenac OphthalmicSuspension); Nitrofurantoin Oral Suspension (Furadantin); Noxafil(Posaconazole Oral Suspension); Nystatin (oral) (Nystatin OralSuspension); Nystatin Oral Suspension (Nystatin (oral)); Ocufen(Flurbiprofen Sodium Ophthalmic Solution); Ofloxacin Ophthalmic Solution(Ofloxacin Ophthalmic Solution); Ofloxacin Otic Solution (Floxin Otic);Olopatadine Hydrochloride Ophthalmic Solution (Pataday); Opticrom(Cromolyn Sodium Ophthalmic Solution); Optipranolol (MetipranololOphthalmic Solution); Patanol; Pediapred; PerioGard; Phenytoin OralSuspension (Dilantin 125); Phisohex; Posaconazole Oral Suspension(Noxafil); Potassium Chloride Extended Release Formulation for LiquidSuspension (Micro-K for Liquid Suspension); Pataday (OlopatadineHydrochloride Ophthalmic Solution); Patanase Nasal Spray (OlopatadineHydrochloride Nasal Spray); PEG Electrolytes Solution (CoLyte);Pemirolast Potassium Ophthalmic Solution (Alamast); Penlac (CiclopiroxTopical Solution); PENNSAID (Diclofenac Sodium Topical Solution);Perforomist (Formoterol Fumarate Inhalation Solution); PeritonealDialysis Solution; Phenylephrine Hydrochloride Ophthalmic Solution(Neo-Synephrine); Phospholine Iodide (Echothiophate Iodide forOphthalmic Solution); Podofilox (Podofilox Topical Solution); Pred Forte(Prednisolone Acetate Ophthalmic Suspension); Pralatrexate Solution forIntravenous Injection (Folotyn); Pred Mild; Prednisone Intensol;Prednisolone Acetate Ophthalmic Suspension (Pred Forte); Prevacid;PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration Solution);ProAir; Proglycem; ProHance (Gadoteridol Injection Solution);Proparacaine Hydrochloride Ophthalmic Solution (Alcaine); Propine;Pulmicort; Pulmozyme; Quixin (Levofloxacin Ophthalmic Solution 0.5%);QVAR; Rapamune; Rebetol; Relacon-HC; Rotarix (Rotavirus Vaccine, Live,Oral Suspension); Rotavirus Vaccine, Live, Oral Suspension (Rotarix);Rowasa (Mesalamine Rectal Suspension Enema); Sabril (Vigabatrin OralSolution); Sacrosidase Oral Solution (Sucraid); Sandimmune; Sepra;Serevent Diskus; Solu Cortef (Hydrocortisone Sodium Succinate); SoluMedrol (Methylprednisolone sodium succinate); Spiriva; Sporanox OralSolution (Itraconazole Oral Solution); Staticin (Erythromycin TopicalSolution 1.5%); Stalevo; Starlix; Sterile HemofiltrationHemodiafiltration Solution (PrismaSol Solution); Stimate; Sucralfate(Carafate Suspension); Sulfacetamide Sodium Ophthalmic Solution 10%(Bleph 10); Synarel Nasal Solution (Nafarelin Acetate Nasal Solution forEndometriosis); Taclonex Scalp (Calcipotriene and BetamethasoneDipropionate Topical Suspension); Tamiflu; Tobi; TobraDex; Tobradex ST(Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05%);Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST);Timolol; Timoptic; Travatan Z; Treprostinil Inhalation Solution(Tyvaso); Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution);Tyvaso (Treprostinil Inhalation Solution); Ventolin; Vfend; VibramycinOral (Doxycycline Calcium Oral Suspension); Videx (Didanosine PediatricPowder for Oral Solution); Vigabatrin Oral Solution (Sabril); Viokase;Viracept; Viramune; Vitamin K1 (Fluid Colloidal Solution of Vitamin K1);Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution); ZarontinOral Solution (Ethosuximide Oral Solution); Ziagen; Zyvox; Zymar(Gatifloxacin Ophthalmic Solution); Zymaxid (Gatifloxacin OphthalmicSolution).

Examples of suitable drug classes to be contained in the lumen 212 ofFIGS. 1 and 2 include: 5-alpha-reductase inhibitors; 5-aminosalicylates;5HT3 receptor antagonists; adamantane antivirals; adrenal corticalsteroids; adrenal corticosteroid inhibitors; adrenergic bronchodilators;agents for hypertensive emergencies; agents for pulmonary hypertension;aldosterone receptor antagonists; alkylating agents;alpha-adrenoreceptor antagonists; alpha-glucosidase inhibitors;alternative medicines; amebicides; aminoglycosides; aminopenicillins;aminosalicylates; amylin analogs; Analgesic Combinations; Analgesics;androgens and anabolic steroids; angiotensin converting enzymeinhibitors; angiotensin II inhibitors; anorectal preparations;anorexiants; antacids; anthelmintics; anti-angiogenic ophthalmic agents;anti-CTLA-4 monoclonal antibodies; anti-infectives; antiadrenergicagents, centrally acting; antiadrenergic agents, peripherally acting;antiandrogens; antianginal agents; antiarrhythmic agents; antiasthmaticcombinations; antibiotics/antineoplastics; anticholinergic antiemetics;anticholinergic antiparkinson agents; anticholinergic bronchodilators;anticholinergic chronotropic agents; anticholinergics/antispasmodics;anticoagulants; anticonvulsants; antidepressants; antidiabetic agents;antidiabetic combinations; antidiarrheals; antidiuretic hormones;antidotes; antiemetic/antivertigo agents; antifungals; antigonadotropicagents; antigout agents; antihistamines; antihyperlipidemic agents;antihyperlipidemic combinations; antihypertensive combinations;antihyperuricemic agents; antimalarial agents; antimalarialcombinations; antimalarial quinolines; antimetabolites; antimigraineagents; antineoplastic detoxifying agents; antineoplastic interferons;antineoplastic monoclonal antibodies; antineoplastics; antiparkinsonagents; antiplatelet agents; antipseudomonal penicillins;antipsoriatics; antipsychotics; antirheumatics; antiseptic andgermicides; antithyroid agents; antitoxins and antivenins;antituberculosis agents; antituberculosis combinations; antitussives;antiviral agents; antiviral combinations; antiviral interferons;anxiolytics, sedatives, and hypnotics; aromatase inhibitors; atypicalantipsychotics; azole antifungals; bacterial vaccines; barbiturateanticonvulsants; barbiturates; BCR-ABL tyrosine kinase inhibitors;benzodiazepine anticonvulsants; benzodiazepines; beta-adrenergicblocking agents; beta-lactamase inhibitors; bile acid sequestrants;biologicals; bisphosphonates; bone resorption inhibitors; bronchodilatorcombinations; bronchodilators; calcitonin; calcium channel blockingagents; carbamate anticonvulsants; carbapenems; carbonic anhydraseinhibitor anticonvulsants; carbonic anhydrase inhibitors; cardiacstressing agents; cardioselective beta blockers; cardiovascular agents;catecholamines; CD20 monoclonal antibodies; CD33 monoclonal antibodies;CD52 monoclonal antibodies; central nervous system agents;cephalosporins; cerumenolytics; chelating agents; chemokine receptorantagonist; chloride channel activators; cholesterol absorptioninhibitors; cholinergic agonists; cholinergic muscle stimulants;cholinesterase inhibitors; CNS stimulants; coagulation modifiers; colonystimulating factors; contraceptives; corticotropin; coumarins andindandiones; cox-2 inhibitors; decongestants; dermatological agents;diagnostic radiopharmaceuticals; dibenzazepine anticonvulsants;digestive enzymes; dipeptidyl peptidase 4 inhibitors; diuretics;dopaminergic antiparkinsonism agents; drugs used in alcohol dependence;echinocandins; EGFR inhibitors; estrogen receptor antagonists;estrogens; expectorants; factor Xa inhibitors; fatty acid derivativeanticonvulsants; fibric acid derivatives; first generationcephalosporins; fourth generation cephalosporins; functional boweldisorder agents; gallstone solubilizing agents; gamma-aminobutyric acidanalogs; gamma-aminobutyric acid reuptake inhibitors; gamma-aminobutyricacid transaminase inhibitors; gastrointestinal agents; generalanesthetics; genitourinary tract agents; GI stimulants; glucocorticoids;glucose elevating agents; glycopeptide antibiotics; glycoproteinplatelet inhibitors; glycylcyclines; gonadotropin releasing hormones;gonadotropin-releasing hormone antagonists; gonadotropins; group Iantiarrhythmics; group II antiarrhythmics; group III antiarrhythmics;group IV antiarrhythmics; group V antiarrhythmics; growth hormonereceptor blockers; growth hormones; H. pylori eradication agents; H2antagonists; hematopoietic stem cell mobilizer; heparin antagonists;heparins; HER2 inhibitors; herbal products; histone deacetylaseinhibitors; hormone replacement therapy; hormones;hormones/antineoplastics; hydantoin anticonvulsants; illicit (street)drugs; immune globulins; immunologic agents; immunosuppressive agents;impotence agents; in vivo diagnostic biologicals; incretin mimetics;inhaled anti-infectives; inhaled corticosteroids; inotropic agents;insulin; insulin-like growth factor; integrase strand transferinhibitor; interferons; intravenous nutritional products; iodinatedcontrast media; ionic iodinated contrast media; iron products;ketolides; laxatives; leprostatics; leukotriene modifiers; lincomycinderivatives; lipoglycopeptides; local injectable anesthetics; loopdiuretics; lung surfactants; lymphatic staining agents; lysosomalenzymes; macrolide derivatives; macrolides; magnetic resonance imagingcontrast media; mast cell stabilizers; medical gas; meglitinides;metabolic agents; methylxanthines; mineralocorticoids; minerals andelectrolytes; miscellaneous agents; miscellaneous analgesics;miscellaneous antibiotics; miscellaneous anticonvulsants; miscellaneousantidepressants; miscellaneous antidiabetic agents; miscellaneousantiemetics; miscellaneous antifungals; miscellaneous antihyperlipidemicagents; miscellaneous antimalarials; miscellaneous antineoplastics;miscellaneous antiparkinson agents; miscellaneous antipsychotic agents;miscellaneous antituberculosis agents; miscellaneous antivirals;miscellaneous anxiolytics, sedatives and hypnotics; miscellaneousbiologicals; miscellaneous bone resorption inhibitors; miscellaneouscardiovascular agents; miscellaneous central nervous system agents;miscellaneous coagulation modifiers; miscellaneous diuretics;miscellaneous genitourinary tract agents; miscellaneous GI agents;miscellaneous hormones; miscellaneous metabolic agents; miscellaneousophthalmic agents; miscellaneous otic agents; miscellaneous respiratoryagents; miscellaneous sex hormones; miscellaneous topical agents;miscellaneous uncategorized agents; miscellaneous vaginal agents;mitotic inhibitors; monoamine oxidase inhibitors; monoclonal antibodies;mouth and throat products; mTOR inhibitors; mTOR kinase inhibitors;mucolytics; multikinase inhibitors; muscle relaxants; mydriatics;narcotic analgesic combinations; narcotic analgesics; nasalanti-infectives; nasal antihistamines and decongestants; nasallubricants and irrigations; nasal preparations; nasal steroids; naturalpenicillins; neuraminidase inhibitors; neuromuscular blocking agents;next generation cephalosporins; nicotinic acid derivatives; nitrates;NNRTIs; non-cardioselective beta blockers; non-iodinated contrast media;non-ionic iodinated contrast media; non-sulfonylureas; nonsteroidalanti-inflammatory agents; norepinephrine reuptake inhibitors;norepinephrine-dopamine reuptake inhibitors; nucleoside reversetranscriptase inhibitors (NRTIs); nutraceutical products; nutritionalproducts; ophthalmic anesthetics; ophthalmic anti-infectives; ophthalmicanti-inflammatory agents; ophthalmic antihistamines and decongestants;ophthalmic diagnostic agents; ophthalmic glaucoma agents; ophthalmiclubricants and irrigations; ophthalmic preparations; ophthalmicsteroids; ophthalmic steroids with anti-infectives; ophthalmic surgicalagents; oral nutritional supplements; otic anesthetics; oticanti-infectives; otic preparations; otic steroids; otic steroids withanti-infectives; oxazolidinedione anticonvulsants; parathyroid hormoneand analogs; penicillinase resistant penicillins; penicillins;peripheral opioid receptor antagonists; peripheral vasodilators;peripherally acting antiobesity agents; phenothiazine antiemetics;phenothiazine antipsychotics; phenylpiperazine antidepressants; plasmaexpanders; platelet aggregation inhibitors; platelet-stimulating agents;polyenes; potassium-sparing diuretics; probiotics; progesterone receptormodulators; progestins; prolactin inhibitors; prostaglandin D2antagonists; protease inhibitors; proton pump inhibitors; psoralens;psychotherapeutic agents; psychotherapeutic combinations; purinenucleosides; pyrrolidine anticonvulsants; quinolones; radiocontrastagents; radiologic adjuncts; radiologic agents; radiologic conjugatingagents; radiopharmaceuticals; RANK ligand inhibitors; recombinant humanerythropoietins; renin inhibitors; respiratory agents; respiratoryinhalant products; rifamycin derivatives; salicylates; sclerosingagents; second generation cephalosporins; selective estrogen receptormodulators; selective serotonin reuptake inhibitors;serotonin-norepinephrine reuptake inhibitors; serotoninergicneuroenteric modulators; sex hormone combinations; sex hormones;skeletal muscle relaxant combinations; skeletal muscle relaxants;smoking cessation agents; somatostatin and somatostatin analogs;spermicides; statins; sterile irrigating solutions; streptomycesderivatives; succinimide anticonvulsants; sulfonamides; sulfonylureas;synthetic ovulation stimulants; tetracyclic antidepressants;tetracyclines; therapeutic radiopharmaceuticals; thiazide diuretics;thiazolidinediones; thioxanthenes; third generation cephalosporins;thrombin inhibitors; thrombolytics; thyroid drugs; tocolytic agents;topical acne agents; topical agents; topical anesthetics; topicalanti-infectives; topical antibiotics; topical antifungals; topicalantihistamines; topical antipsoriatics; topical antivirals; topicalastringents; topical debriding agents; topical depigmenting agents;topical emollients; topical keratolytics; topical steroids; topicalsteroids with anti-infectives; toxoids; triazine anticonvulsants;tricyclic antidepressants; trifunctional monoclonal antibodies; tumornecrosis factor (TNF) inhibitors; tyrosine kinase inhibitors; ultrasoundcontrast media; upper respiratory combinations; urea anticonvulsants;urinary anti-infectives; urinary antispasmodics; urinary pH modifiers;uterotonic agents; vaccine; vaccine combinations; vaginalanti-infectives; vaginal preparations; vasodilators; vasopressinantagonists; vasopressors; VEGF/VEGFR inhibitors; viral vaccines;viscosupplementation agents; vitamin and mineral combinations; vitamins.

Examples of suitable diagnostic tests to be contained in the lumen 212of FIGS. 1 and 2 include: 17-Hydroxyprogesterone; ACE (Angiotensin Iconverting enzyme); Acetaminophen; Acid phosphatase; ACTH; Activatedclotting time; Activated protein C resistance; Adrenocorticotropichormone (ACTH); Alanine aminotransferase (ALT); Albumin; Aldolase;Aldosterone; Alkaline phosphatase; Alkaline phosphatase (ALP);Alpha1-antitrypsin; Alpha-fetoprotein; Alpha-fetoprotien; Ammonialevels; Amylase; ANA (antinuclear antbodies); ANA (antinuclearantibodies); Angiotensin-converting enzyme (ACE); Anion gap;Anticardiolipin antibody; Anticardiolipin antivbodies (ACA);Anti-centromere antibody; Antidiuretic hormone; Anti-DNA; Anti-Dnase-B;Anti-Gliadin antibody; Anti-glomerular basement membrane antibody;Anti-HBc (Hepatitis B core antibodies; Anti-HBs (Hepatitis B surfaceantibody; Antiphospholipid antibody; Anti-RNA polymerase; Anti-Smith(Sm) antibodies; Anti-Smooth Muscle antibody; Antistreptolysin 0 (ASO);Antithrombin III; Anti-Xa activity; Anti-Xa assay; Apolipoproteins;Arsenic; Aspartate aminotransferase (AST); B12; Basophil;Beta-2-Microglobulin; Beta-hydroxybutyrate; B-HCG; Bilirubin; Bilirubin,direct; Bilirubin, indirect; Bilirubin, total; Bleeding time; Bloodgases (arterial); Blood urea nitrogen (BUN); BUN; BUN (blood ureanitrogen); CA 125; CA 15-3; CA 19-9; Calcitonin; Calcium; Calcium(ionized); Carbon monoxide (CO); Carcinoembryonic antigen (CEA); CBC;CEA; CEA (carcinoembryonic antigen); Ceruloplasmin; CH50Chloride;Cholesterol; Cholesterol, HDL; Clot lysis time; Clot retraction time;CMP; CO2; Cold agglutinins; Complement C3; Copper; Corticotrophinreleasing hormone (CRH) stimulation test; Cortisol; Cortrosynstimulation test; C-peptide; CPK (Total); CPK-MB; C-reactive protein;Creatinine; Creatinine kinase (CK); Cryoglobulins; DAT (Directantiglobulin test); D-Dimer; Dexamethasone suppression test; DHEA-S;Dilute Russell viper venom; Elliptocytes; Eosinophil; Erythrocytesedimentation rate (ESR); Estradiol; Estriol; Ethanol; Ethylene glycol;Euglobulin lysis; Factor V Leiden; Factor VIII inhibitor; Factor VIIIlevel; Ferritin; Fibrin split products; Fibrinogen; Folate; Folate(serum; Fractional excretion of sodium (FENA); FSH (follicle stimulatingfactor); FTA-ABS; Gamma glutamyl transferase (GGT); Gastrin; GGTP (Gammaglutamyl transferase); Glucose; Growth hormone; Haptoglobin; HBeAg(Hepatitis Be antigen); HBs-Ag (Hepatitis B surface antigen);Helicobacter pylori; Hematocrit; Hematocrit (HCT); Hemoglobin;Hemoglobin A1C; Hemoglobin electrophoresis; Hepatitis A antibodies;Hepatitis C antibodies; IAT (Indirect antiglobulin test); Immunofixation(IFE); Iron; Lactate dehydrogenase (LDH); Lactic acid (lactate); LDH; LH(Leutinizing hormone; Lipase; Lupus anticoagulant; Lymphocyte;Magnesium; MCH (mean corpuscular hemoglobin; MCHC (mean corpuscularhemoglobin concentration); MCV (mean corpuscular volume);Methylmalonate; Monocyte; MPV (mean platelet volume); Myoglobin;Neutrophil; Parathyroid hormone (PTH); Phosphorus; Platelets (plt);Potassium; Prealbumin; Prolactin; Prostate specific antigen (PSA);Protein C; Protein S; PSA (prostate specific antigen); PT (Prothrombintime); PTT (Partial thromboplastin time); RDW (red cell distributionwidth); Renin; Rennin; Reticulocyte count; reticulocytes; Rheumatoidfactor (RF); Sed Rate; Serum glutamic-pyruvic transaminase (SGPT; Serumprotein electrophoresis (SPEP); Sodium; T3-resin uptake (T3RU); T4,Free; Thrombin time; Thyroid stimulating hormone (TSH); Thyroxine (T4);Total iron binding capacity (TIBC); Total protein; Transferrin;Transferrin saturation; Triglyceride (TG); Troponin; Uric acid; VitaminB12; White blood cells (WBC); Widal test.

Even another embodiment is a medical or diagnostic kit including avessel having a pH protective coating or layer as defined in anyembodiment herein on a substrate as defined in any embodiment above.Optionally, the kit additionally includes a medicament or diagnosticagent which is contained in the vessel; and/or a hypodermic needle,double-ended needle, or other delivery conduit; and/or an instructionsheet.

Vessel Containing Viable Blood, Having a Primer Coating or LayerDeposited from an Organosilicon Precursor

Even another embodiment is a blood containing vessel. Severalnon-limiting examples of such a vessel are a blood transfusion bag, ablood sample collection vessel in which a sample has been collected, thetubing of a heart-lung machine, a flexible-walled blood collection bag,or tubing used to collect a patient's blood during surgery andreintroduce the blood into the patient's vasculature. If the vesselincludes a pump for pumping blood, a particularly suitable pump is acentrifugal pump or a peristaltic pump. The vessel has a wall; the wallhas an inner or interior surface defining a lumen. The inner or interiorsurface of the wall has an at least partial primer coating or layer of aprotective layer, which optionally also presents a hydrophobic surface.The primer coating or layer can be as thin as monomolecular thickness oras thick as about 1000 nm. The vessel contains blood viable for returnto the vascular system of a patient disposed within the lumen in contactwith the hydrophobic layer.

An embodiment is a blood containing vessel including a wall and havingan inner or interior surface defining a lumen. The inner or interiorsurface has an at least partial primer coating or layer that optionallyalso presents a hydrophobic surface. The primer coating or layer canalso comprise or consist essentially of SiO_(x)C_(y) where x and y areas defined in this specification. The thickness of the hydrophobiccoating or layer is within the range from monomolecular thickness toabout 1000 nm thick on the inner or interior surface. The vesselcontains blood viable for return to the vascular system of a patientdisposed within the lumen in contact with the hydrophobic coating orlayer.

Primer Coating or Layer Deposited from an Organosilicon PrecursorReduces Clotting or Platelet Activation of Blood in the Vessel

Another embodiment is a vessel having a wall. The wall has an inner orinterior surface defining a lumen and has an at least partial primercoating or layer that presents a hydrophobic surface, where optionally xand y are as previously defined. The thickness of the primer coating orlayer is from monomolecular thickness to about 1000 nm thick on theinner or interior surface. The primer coating or layer is effective toreduce the clotting or platelet activation of blood exposed to the inneror interior surface, compared to the same type of wall uncoated with ahydrophobic layer.

It is contemplated that the incorporation of a hydrophobic layer willreduce the adhesion or clot forming tendency of the blood, as comparedto its properties in contact with an unmodified polymeric or SiO_(x)surface. This property is contemplated to reduce or potentiallyeliminate the need for treating the blood with heparin, as by reducingthe necessary blood concentration of heparin in a patient undergoingsurgery of a type requiring blood to be removed from the patient andthen returned to the patient, as when using a heart-lung machine duringcardiac surgery. It is contemplated that this will reduce thecomplications of surgery involving the passage of blood through such apharmaceutical package or other vessel, by reducing the bleedingcomplications resulting from the use of heparin.

Another embodiment is a vessel including a wall and having an inner orinterior surface defining a lumen. The inner or interior surface has anat least partial primer coating or layer that presents a hydrophobicsurface, the thickness of the primer coating or layer being frommonomolecular thickness to about 1000 nm thick on the inner or interiorsurface, the primer coating or layer being effective to reduce theclotting or platelet activation of blood exposed to the inner orinterior surface.

Vessel Containing Viable Blood, Having a Primer Coating or Layer ofGroup III or IV Element

Another embodiment is a blood containing vessel having a wall having aninner or interior surface defining a lumen. The inner or interiorsurface has an at least partial primer coating or layer of a compositioncomprising one or more elements of Group III, one or more elements ofGroup IV, or a combination of two or more of these. The thickness of theprimer coating or layer is between monomolecular thickness and about1000 nm thick, inclusive, on the inner or interior surface. The vesselcontains blood viable for return to the vascular system of a patientdisposed within the lumen in contact with the primer coating or layer.

Primer Coating or Layer of Group III or IV Element Reduces Clotting orPlatelet Activation of Blood in the Vessel

Optionally, in the vessel of the preceding paragraph, the primer coatingor layer of the Group III or IV Element is effective to reduce theclotting or platelet activation of blood exposed to the inner orinterior surface of the vessel wall.

Insulin Vessel

As one option, the compound or a component of the composition isinsulin, and precipitation of the insulin is prevented or reduced. Asanother option, the compound or a component of the composition is bloodor a blood fraction, and blood clotting or platelet activation isprevented or reduced. As still another option, the vessel with a primercoating or layer is a blood collection tube. Optionally, the bloodcollection tube can contain an agent for preventing blood clotting orplatelet activation, for example ethylenediamineteetraacetic acid(EDTA), a sodium salt thereof, or heparin.

The use of a coated substrate according to any described embodiment iscontemplated for storing insulin.

Protocols and Test Methods

Atomic Composition

The atomic compositions of the tie coating or layer, the barrier coatingor layer, and the pH protective coating or layer are characterized usingX-Ray Photoelectron Spectroscopy (XPS), to measure silicon, oxygen, andcarbon, and either Rutherford backscattering (RBS) or hydrogen forwardscattering (HFS) spectrometry to measure hydrogen. A separate analyticalmethod is used to determine the hydrogen content because XPS does notdetect hydrogen. The following methods are used, unless otherwiseexpressly indicated.

XPS Protocol

XPS data is quantified using relative sensitivity factors and a modelthat assumes a homogeneous layer. The analysis volume is the product ofthe analysis area (spot size or aperture size) and the depth ofinformation. Photoelectrons are generated within the X-ray penetrationdepth (typically many microns), but only the photoelectrons within thetop three photoelectron escape depths are detected. Escape depths are onthe order of 15-35 Å, which leads to an analysis depth of −50-100 Å.Typically, 95% of the signal originates from within this depth.

The following analytical parameters are used:

-   -   Instrument: PHI Quantum 2000    -   X-ray source: Monochromated Alka 1486.6 eV    -   Acceptance Angle+23°    -   Take-off angle 45°    -   Analysis area 600 μm    -   Charge Correction C1s 284.8 eV    -   Ion Gun Conditions Ar+, 1 keV, 2×2 mm raster    -   Sputter Rate 15.6 Å/min (SiO2 Equivalent)

Values given are normalized to 100 percent using the elements detected.Detection limits are approximately 0.05 to 1.0 atomic percent.

Rutherford Backscattering Spectrometry (RBS)

RBS spectra are acquired at a backscattering angle of 160° and anappropriate grazing angle (with the sample oriented perpendicular to theincident ion beam). The sample is rotated or tilted with a small angleto present a random geometry to the incident beam. This avoidschanneling in both the film and the substrate. The use of two detectorangles can significantly improve the measurement accuracy forcomposition when thin surface layers need to be analyzed.

When a thin (<100 nm) amorphous or polycrystalline film resides on asingle crystal substrate “ion channeling” may be utilized to reduce thebackscattering signal from the substrate. This results in improvedaccuracy in the composition of layers containing elements that overlaywith the substrate signal, typically light elements such as oxygen,nitrogen and carbon.

Analytical Parameters: RBS

-   -   He++ Ion Beam Energy 2.275 MeV    -   Normal Detector Angle 160°    -   Grazing Detector Angle −100°    -   Analysis Mode CC RR

Spectra are fit by applying a theoretical layer model and iterativelyadjusting elemental concentrations and thickness until good agreement isfound between the theoretical and the experimental spectra.

Hydrogen Forward Scattering Spectrometry (HFS)

In an HFS experiment a detector is placed 30° from the forwardtrajectory of the incident He++ ion beam and the sample is rotated sothat the incident beam strikes the surfaces 75° from normal. In thisgeometry it is possible to collect light atoms, namely hydrogen,forward-scattered from a sample after collisions with the probing He++ion beam. A thin absorber foil is placed over the detector to filter outHe++ ions that are also forward scattered from the sample.

Hydrogen concentrations are determined by comparing the number ofhydrogen counts obtained from reference samples after normalizing by thestopping powers of the different materials. A hydrogen implanted siliconsample and a geological sample, muscovite, are used as references. Thehydrogen concentration in the hydrogen implanted silicon sample is takento be its stated implant dose of 1.6×1017±0.2×1017 atoms/cm². Themuscovite (MUSC) sample is known to have ˜6.5±0.5 atomic percenthydrogen.

Samples are checked for hydrogen loss in the analyzed region. This isdone by acquiring spectra for different acquisition times (initially ashort exposure followed by a longer exposure to the He++ beam). Chargeaccumulations for 5 and 40 μC are used. A lower proportional signal inthe 40 μC spectrum indicates hydrogen loss. In those cases the shorterexposure is chosen for analysis at the expense of higher noise in thespectrum. To account for surface hydrogen due to residual moisture orhydrocarbon adsorption a silicon control sample is analyzed togetherwith the actual samples and the hydrogen signal from the control sampleis subtracted from each of the spectra obtained from the actual samples.During the HFS acquisition backscattering spectra are acquired using the160° angle detector (with the sample in forward scattering orientation).The RBS spectra are used to normalize the total charge delivered to thesample.

Analytical Parameters: HFS

-   -   He++ Ion Beam Energy 2.275 MeV    -   Normal Detector Angle 160°    -   Grazing Detector Angle −30°    -   Ion Beam to Sample Normal 75°        Protocol for Total Silicon Measurement

This protocol is used to determine the total amount of silicon coatingspresent on the entire vessel wall. A supply of 0.1 N potassium hydroxide(KOH) aqueous solution is prepared, taking care to avoid contact betweenthe solution or ingredients and glass. The water used is purified water,18 MΩ quality. A Perkin Elmer Optima Model 7300DV ICP-OES instrument isused for the measurement except as otherwise indicated.

Each device (vial, syringe, tube, or the like) to be tested and its capand crimp (in the case of a vial) or other closure are weighed empty to0.001 g, then filled completely with the KOH solution (with noheadspace), capped, crimped, and reweighed to 0.001 g. In a digestionstep, each vial is placed in an autoclave oven (liquid cycle) at 121° C.for 1 hour. The digestion step is carried out to quantitatively removethe silicon coatings from the vessel wall into the KOH solution. Afterthis digestion step, the vials are removed from the autoclave oven andallowed to cool to room temperature. The contents of the vials aretransferred into ICP tubes. The total Si concentration is run on eachsolution by ICP/OES following the operating procedure for the ICP/OES.

The total Si concentration is reported as parts per billion of Si in theKOH solution. This concentration represents the total amount of siliconcoatings that were on the vessel wall before the digestion step was usedto remove it.

The total Si concentration can also be determined for fewer than all thesilicon layers on the vessel, as when an SiO_(x) barrier layer isapplied, an SiO_(x)C_(y) second layer (for example, a lubricity layer ora pH protective coating or layer) is then applied, and it is desired toknow the total silicon concentration of just the SiO_(x)C_(y) layer.This determination is made by preparing two sets of vessels, one set towhich only the SiO_(x) layer is applied and the other set to which thesame SiO_(x) layer is applied, followed by the SiO_(x)C_(y) layer orother layers of interest. The total Si concentration for each set ofvessels is determined in the same manner as described above. Thedifference between the two Si concentrations is the total Siconcentration of the SiO_(x)C_(y) second layer.

Protocol for Measuring Dissolved Silicon in a Vessel

In some of the working examples, the amount of silicon dissolved fromthe wall of the vessel by a test solution is determined, in parts perbillion (ppb), for example to evaluate the dissolution rate of the testsolution. This determination of dissolved silicon is made by storing thetest solution in a vessel provided with an SiO_(x) and/or SiO_(x)C_(y)coating or layer under test conditions, then removing a sample of thesolution from the vessel and testing the Si concentration of the sample.The test is done in the same manner as the Protocol for Total SiliconMeasurement, except that the digestion step of that protocol is replacedby storage of the test solution in the vessel as described in thisprotocol. The total Si concentration is reported as parts per billion ofSi in the test solution

Protocol for Determining Average Dissolution Rate

As shown in the working examples, the silicon dissolution rate ismeasured by determining the total silicon leached from the vessel intoits contents, and does not distinguish between the silicon derived fromthe pH protective coating or layer 286, the lubricity layer 281, thebarrier coating or layer 288, or other materials present.

The average dissolution rates reported in the working examples aredetermined as follows. A series of test vessels having a known totaltotal silicon measurement are filled with the desired test solutionanalogous to the manner of filling the vials with the KOH solution inthe Protocol for Total Silicon Measurement. (The test solution can be aphysiologically inactive test solution as employed in the presentworking examples or a physiologically active pharmaceutical preparationintended to be stored in the vessels to form a pharmaceutical package).The test solution is stored in respective vessels for several differentamounts of time, then analyzed for the Si concentration in parts perbillion in the test solution for each storage time. The respectivestorage times and Si concentrations are then plotted. The plots arestudied to find a series of substantially linear points having thesteepest slope.

The plot of dissolution amount (ppb Si) versus days decreases in slopewith time, even though it does not appear that the Si layer has beenfully digested by the test solution.

For the PC194 test data in Table 10 below, linear plots of dissolutionversus time data are prepared by using a least squares linear regressionprogram to find a linear plot corresponding to the first five datapoints of each of the experimental plots. The slope of each linear plotis then determined and reported as representing the average dissolutionrate applicable to the test, measured in parts per billion of Sidissolved in the test solution per unit of time.

Protocol for Determining Calculated Shelf Life

The calculated shelf life values reported in the working examples beloware determined by extrapolation of the total silicon measurements andaverage dissolution rates, respectively determined as described in theProtocol for Total Silicon Measurement and the Protocol for DeterminingAverage Dissolution Rate. The assumption is made that under theindicated storage conditions the SiO_(x)C_(y) pH protective coating orlayer will be removed at the average dissolution rate until the coatingis entirely removed. Thus, the total silicon measurement for the vessel,divided by the dissolution rate, gives the period of time required forthe test solution to totally dissolve the SiO_(x)C_(y) coating. Thisperiod of time is reported as the calculated shelf life. Unlikecommercial shelf life calculations, no safety factor is calculated.Instead, the calculated shelf life is the calculated time to failure.

It should be understood that because the plot of ppb Si versus hoursdecreases in slope with time, an extrapolation from relatively shortmeasurement times to relatively long calculated shelf lives is believedto be a “worst case” test that tends to underestimate the calculatedshelf life actually obtainable.

Measurement of Coating Thickness

The thickness of a PECVD coating or layer such as the pH protectivecoating or layer, the barrier coating or layer, the lubricity coating orlayer, and/or a composite of any two or more of these layers can bemeasured, for example, by transmission electron microscopy (TEM). Anexemplary TEM image for a pH protective coating or layer is shown inFIG. 17. An exemplary TEM image for an SiO₂ barrier coating or layer isshown in FIG. 18.

The TEM can be carried out, for example, as follows. Samples can beprepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Eitherthe samples can be first coated with a thin layer of carbon (50-100 nmthick) and then coated with a sputtered coating or layer of platinum(50-100 nm thick) using a K575X Emitech primer coating or layer system,or the samples can be coated directly with the protective sputtered Ptlayer. The coated samples can be placed in an FEI FIB200 FIB system. Anadditional coating or layer of platinum can be FIB-deposited byinjection of an organometallic gas while rastering the 30 kV gallium ionbeam over the area of interest. The area of interest for each sample canbe chosen to be a location half way down the length of the syringebarrel. Thin cross sections measuring approximately 15 μm(“micrometers”) long, 2 μm wide and 15 μm deep can be extracted from thedie surface using an in-situ FIB lift-out technique. The cross sectionscan be attached to a 200 mesh copper TEM grid using FIB-depositedplatinum. One or two windows in each section, measuring about 8 μm wide,can be thinned to electron transparency using the gallium ion beam ofthe FEI FIB.

Cross-sectional image analysis of the prepared samples can be performedutilizing either a Transmission Electron Microscope (TEM), or a ScanningTransmission Electron Microscope (STEM), or both. All imaging data canbe recorded digitally. For STEM imaging, the grid with the thinned foilscan be transferred to a Hitachi HD2300 dedicated STEM. Scanningtransmitted electron images can be acquired at appropriatemagnifications in atomic number contrast mode (ZC) and transmittedelectron mode (TE). The following instrument settings can be used.

Scanning Transmission Electron Instrument Microscope Manufacturer/ModelHitachi HD2300 Accelerating Voltage 200 kV Objective Aperture 2Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747Approximate Objective Lens Setting 5.86 ZC Mode Projector Lens 1.149 TEMode Projector Lens 0.7 Image Acquisition Pixel Resolution 1280 × 960Acquisition Time 20 sec. (x4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000transmission electron microscope. Transmitted electron images can beacquired at appropriate magnifications. The relevant instrument settingsused during image acquisition can be those given below.

Instrument Transmission Electron Microscope Manufacturer/Model HitachiHF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens2 0 Objective Lens 6.34 Condenser Lens Aperture 1

Instrument Transmission Electron Microscope Objective Lens Aperture forimaging 3 Selective Area Aperture for SAD N/ASEM Procedure

SEM Sample Preparation: Each syringe sample was cut in half along itslength (to expose the inner or interior surface). The top of the syringe(Luer end) was cut off to make the sample smaller.

The sample was mounted onto the sample holder with conductive graphiteadhesive, then put into a Denton Desk IV SEM Sample Preparation System,and a thin (approximately 50 Å) gold coating was sputtered onto theinner or interior surface of the syringe. The gold coating is used toeliminate charging of the surface during measurement.

The sample was removed from the sputter system and mounted onto thesample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). Thesample was pumped down to at least 1×10-6 Torr in the samplecompartment. Once the sample reached the required vacuum level, the slitvalve was opened and the sample was moved into the analysis station.

The sample was imaged at a coarse resolution first, then highermagnification images were accumulated. The SEM images provided in theFigures are 5 μm edge-to-edge (horizontal and vertical).

AFM (Atomic Force Microscopy) Procedure.

AFM images were collected using a NanoScope III Dimension 3000 machine(Digital Instruments, Santa Barbara, Calif., USA). The instrument wascalibrated against a NIST traceable standard. Etched silicon scanningprobe microscopy (SPM) tips were used. Image processing proceduresinvolving auto-flattening, plane fitting or convolution were employed.One 10 μm×10 μm area was imaged. Roughness analyses were performed andwere expressed in: (1) Root-Mean-Square Roughness, RMS; 2 MeanRoughness, Ra; and (3) Maximum Height (Peak-to-Valley), Rmax, allmeasured in nm (see Table 5 and FIGS. 8 to 16. For the roughnessanalyses, each sample was imaged over the 10 μm×10 μm area, followed bythree cross sections selected by the analyst to cut through features inthe 10 μm×10 μm images. The vertical depth of the features was measuresusing the cross section tool. For each cross section, a Root-Mean-SquareRoughness (RMS) in nanmeters was reported. These RMS values along withthe average of the three cross sections for each sample are listed inTable 5.

Additional analysis of the 10 μm×10 μm images represented by FIGS. 8 to16 (Examples Q, T and V) was carried out. For this analysis three crosssections were extracted from each image. The locations of the crosssections were selected by the analyst to cut through features in theimages. The vertical depth of the features was measured using the crosssection tool.

The Digital Instruments Nanoscope III AFM/STM acquires and stores3-dimensional representations of surfaces in a digital format. Thesesurfaces can be analyzed in a variety of ways.

The Nanoscope III software can perform a roughness analysis of any AFMor STM image. The product of this analysis is a single page reproducingthe selected image in top view. To the upper right of the image is the“Image Statistics” box, which lists the calculated characteristics ofthe whole image minus any areas excluded by a stopband (a box with an Xthrough it). Similar additional statistics can be calculated for aselected portion of the image and these are listed in the “BoxStatistics” in the lower right portion of the page. What follows is adescription and explanation of these statistics.

Image Statistics:

Z Range (Rp): The difference between the highest and lowest points inthe image. The value is not corrected for tilt in the plane of theimage; therefore, plane fitting or flattening the data will change thevalue.

Mean: The average of all of the Z values in the imaged area. This valueis not corrected for the tilt in the plane of the image; therefore,plane fitting or flattening the data will change this value.

RMS (Rq): This is the standard deviation of the Z values (or RMSroughness) in the image. It is calculated according to the formula:Rq={Σ(Z1−Zavg)2/N}

where Zavg is the average Z value within the image; Z1 is the currentvalue of Z; and N is the number of points in the image. This value isnot corrected for tilt in the plane of the image; therefore, planefitting or flattening the data will change this value.

Mean roughness (Ra): This is the mean value of the surface relative tothe Center Plane and is calculated using the formula:Ra=[1/(LxLy)]∫oLy∫oLx{f(x,y)}dxdy

where f(x,y) is the surface relative to the Center plane, and Lx and Lyare the dimensions of the surface.

Max height (Rmax): This is the difference in height between the highestand lowest points of the surface relative to the Mean Plane.

Surface area: (Optical calculation): This is the area of the3-dimensional surface of the imaged area. It is calculated by taking thesum of the areas of the triangles formed by 3 adjacent data pointsthroughout the image.

Surface area diff: (Optional calculation) This is the amount that theSurface area is in excess of the imaged area. It is expressed as apercentage and is calculated according to the formula:Surface area diff=100[(Surface area/S12−1]

where S1 is the length (and width) of the scanned area minus any areasexcluded by stopbands.

Center Plane: A flat plane that is parallel to the Mean Plane. Thevolumes enclosed by the image surface above and below the center planeare equal.

Mean Plane: The image data has a minimum variance about this flat plane.It results from a first order least squares fit on the Z data.

EXAMPLES Examples 1-4—Conditions for Production of pH Protective Layer

Some conditions used for production of pH Protective Layers are shown inTable 1.

TABLE 1 OMCTS-BASED PLASMA pH PROTECTIVE COATING OR LAYER MADE WITHCARRIER GAS pH protective protective protective Carrier pH protective pHprotective coating or OMCTS O2 Gas (Ar) coating or coating or PHprotective layer Time Flow Rate Flow Rate Flow Rate layer Power Examplelayer Type Monomer (sec) (sccm) (sccm) (sccm) (Watts) 1 Uncoated n/a n/an/a n/a n/a n/a (Control) COC 2 Silicon oil n/a n/a n/a n/a n/a n/a(Industry on COC Standard) 3 L3 lubricity OMCTS 10 sec 3 0 65 6 (withoutcoating or Oxygen) layer over SiO_(x) on COC 4 L2 pH OMCTS 10 sec 3 1 656 (with protective Oxygen) coating or layer over SiO_(x) on COC

Examples 5-8

Syringe samples were produced as follows. A COC 8007 extended barrelsyringe was produced according to the Protocol for Forming COC SyringeBarrel. An SiO_(x) barrier coating or layer was applied to the syringebarrels according to the Protocol for Coating COC Syringe BarrelInterior with SiO_(x). A pH protective coating or layer was applied tothe SiO_(x) coated syringes according to the Protocol for Coating COCSyringe Barrel Interior with OMCTS, modified as follows. Argon carriergas and oxygen were used where noted in Table 2. The process conditionswere set to the following, or as indicated in Table 2:

-   -   OMCTS—3 sccm (when used)    -   Argon gas—7.8 sccm (when used)    -   Oxygen 0.38 sccm (when used)    -   Power—3 watts    -   Power on time—10 seconds        Syringes of Examples 5, 6, and 7 were tested to determine total        extractable silicon levels (representing extraction of the        organosilicon-based PECVD pH protective coating or layer) using        the Protocol for Measuring Dissolved Silicon in a Vessel,        modified and supplemented as shown in this example.

The silicon was extracted using saline water digestion. The tip of eachsyringe plunger was covered with PTFE tape to prevent extractingmaterial from the elastomeric tip material, then inserted into thesyringe barrel base. The syringe barrel was filled with two millilitersof 0.9% aqueous saline solution via a hypodermic needle inserted throughthe Luer tip of the syringe. This is an appropriate test forextractables because many prefilled syringes are used to contain anddeliver saline solution. The Luer tip was plugged with a piece of PTFEbeading of appropriate diameter. The syringe was set into a PTFE teststand with the Luer tip facing up and placed in an oven at 50° C. for 72hours.

Then, either a static or a dynamic mode was used to remove the salinesolution from the syringe barrel. According to the static mode indicatedin Table 2, the syringe plunger was removed from the test stand, and thefluid in the syringe was decanted into a vessel. According to thedynamic mode indicated in Table 2, the Luer tip seal was removed and theplunger was depressed to push fluid through the syringe barrel and expelthe contents into a vessel. In either case, the fluid obtained from eachsyringe barrel was brought to a volume of 50 ml using 18.2MΩ-cmdeionized water and further diluted 2× to minimize sodium backgroundduring analysis. The CVH barrels contained two milliliters and thecommercial barrels contained 2.32 milliliters.

Next, the fluid recovered from each syringe was tested for extractablesilicon using the Protocol for Measuring Dissolved Silicon in a Vessel.The instrument used was a Perkin Elmer Elan DRC II equipped with a CetacASX-520 autosampler. The following ICP-MS conditions were employed:

-   -   Nebulizer: Quartz Meinhardt    -   Spray Chamber: Cyclonic    -   RF (radio frequency) power: 1550 Watts    -   Argon (Ar) Flow: 15.0 L/min    -   Auxiliary Ar Flow: 1.2 L/min    -   Nebulizer Gas Flow: 0.88 L/min    -   Integration time: 80 sec    -   Scanning mode: Peak hopping    -   RPq (The RPq is a rejection parameter) for Cerium as CeO (m/z        156: <2%

Aliquots from aqueous dilutions obtained from Syringes E, F, and G wereinjected and analyzed for Si in concentration units of micrograms perliter. The results of this test are shown in Table 2. While the resultsare not quantitative, they do indicate that extractables from the pHprotective coating or layer are not clearly higher than the extractablesfor the SiO_(x) barrier layer only. Also, the static mode produced farless extractables than the dynamic mode, which was expected.

TABLE 2 OMCTS PH PROTECTIVE COATING OR LAYER (E and F) OMCTS O₂ ArExample (sccm) (sccm) (sccm) 5 3.0 0.38 7.8 6 3.0 0.38 7.8 7 n/a n/a n/a(SiO_(x)only) 8 n/a n/a n/a (silicon oil)

Examples 9-11

Syringe Examples 9, 10, and 11, employing three different pH protectivecoatings or layers, were produced in the same manner as for Examples 5-8except as follows or as indicated in Table 3:

-   -   OMCTS—2.5 sccm    -   Argon gas—7.6 sccm (when used)    -   Oxygen 0.38 sccm (when used)    -   Power—3 watts    -   Power on time—10 seconds

Syringe Example 9 had a three-component pH protective coating or layeremploying OMCTS, oxygen, and carrier gas. Syringe Example 10 had a twocomponent pH protective coating or layer employing OMCTS and oxygen, butno carrier gas. Syringe Example 11 had a one-component pH protectivecoating or layer (OMCTS only). Syringes of Examples 9-11 were thentested for lubricity as described for Examples 5-8.

The pH protective coatings or layers produced according to these workingexamples are also contemplated to function as protective coatings orlayers to increase the shelf life of the vessels, compared to similarvessels provided with a barrier coating or layer but no pH protectivecoating or layer.

TABLE 3 OMCTS pH protective coating or layer OMCTS -2.5 sccm Argon gas-7.6 sccm (when used) Oxygen 0.38 sccm (when used) Power - 3 watts Poweron time - 10 seconds

Examples 12-14

Examples 9-11 using an OMCTS precursor gas were repeated in Examples12-14, except that HMDSO was used as the precursor in Examples 12-14.The results are shown in Table 4. The coatings produced according tothese working examples are contemplated to function as pH protectivecoatings or layers, and also as protective coatings or layers toincrease the shelf life of the vessels, compared to similar vesselsprovided with a barrier coating or layer but no pH protective coating orlayer.

TABLE 4 HMDSO pH protective coating or layer HMDSO O₂ Ar Example (sccm)(sccm) (sccm) 12 2.5 0.38 7.6 13 2.5 0.38 — 14 2.5 — —

The pH protective coatings or layers produced according to these workingexamples are also contemplated to function as protective coatings orlayers to increase the shelf life of the vessels, compared to similarvessels provided with a barrier coating or layer but no pH protectivecoating or layer.

TABLE 5 Dep. OMCTS Ar/O₂ Power Time AFM RMS Example (sccm) (sccm)(Watts) (sec) (nanometers) 15 2.0 10/0.38 3.5 10 16 17 19.6, 9.9, 9.4(Average = 13.0 21 2.0 10/0.38 4.5 10 22 FIG. 7 23 12.5, 8.4, 6.1(Average = 6.3) 24 2.0 10/0   3.4 10 25 1.9, 2.6, 3.0 (Average = 2.3)

TABLE 6 Siloxane Power Dep. Time SiO_(x)/Lub Coater Mode Feed Ar/O₂ (W)(Sec.) Example 18 SiO_(x): Auto-Tube Auto HMDSO 0 sccm Ar, 37 7SiO_(x)/Baseline 52.5 in, 90 sccm O₂ OMCTS Lub 133.4 cm. Lubricity:Auto-S same OMCTS, 10 sccm Ar 3.4 10 2.0 sccm 0.38 sccm O₂ Example 19SiO_(x): same same same same 37 7 SiO_(x)/High Pwr OMCTS Lub Lubricity:same same same same 4.5 10 Example 20 SiO_(x): Auto-Tube same same 0sccm Ar, 37 7 SiO_(x)/No O₂ 90 sccm O₂ OMCTS Lub Lubricity: Auto-S samesame 10 sccm Ar 3.4 10 0 sccm O₂Summary of Lubricity and/or Protective Measurements

[Table 8 shows a summary of the above OMCTS coatings or layers

TABLE 8 Summary Table of OMCTS PH PROTECTIVE COATING OR LAYER fromTables 1, 2, 3 and 5 OMCTS O₂ Ar Power Dep Time Example (sccm) (sccm)(sccm) (Watt) (sec)  3 3.0 0.00 65 6 10  4 3.0 1.00 65 6 10  5 3.0 0.387.8 6 10  6 3.0 0.38 7.8 6 10  9 2.5 0.38 7.6 6 10 10 2.5 0.38 0.0 6 1011 2.5 0.00 0.0 6 10 15 2.0 0.38 10 3.5 10 16 2.0 0.38 10 4.5 10   16A2.0 0.00 10 3.4 10 18 2.0 0.38 10 3.4 10 19 2.0 0.38 10 4.5 10 20 2.00.00 10 3.4 10

Comparative Example 26: Dissolution of SiO_(x) Coating Versus pH

The Protocol for Measuring Dissolved Silicon in a Vessel is followed,except as modified here. Test solutions—50 mM buffer solutions at pH 3,6, 7, 8, 9, and 12 are prepared. Buffers are selected having appropriatepKa values to provide the pH values being studied. A potassium phosphatebuffer is selected for pH 3, 7, 8 and 12, a sodium citrate buffer isutilized for pH 6 and tris buffer is selected for pH 9. 3 ml of eachtest solution is placed in borosilicate glass 5 ml pharmaceutical vialsand SiO_(x) coated 5 ml thermoplastic pharmaceutical vials. The vialsare all closed with standard coated stoppers and crimped. The vials areplaced in storage at 20-25° C. and pulled at various time points forinductively coupled plasma spectrometer (ICP) analysis of Si content inthe solutions contained in the vials, in parts per billion (ppb) byweight, for different storage times.

The Protocol for Determining Average Dissolution Rate Si content is usedto monitor the rate of glass dissolution, except as modified here. Thedata is plotted to determine an average rate of dissolution ofborosilicate glass or SiO_(x) coating at each pH condition.Representative plots at pH 6 through 8 are FIGS. 27-29.

The rate of Si dissolution in ppb is converted to a predicted thickness(nm) rate of Si dissolution by determining the total weight of Siremoved, then using a surface area calculation of the amount of vialsurface (11.65 cm2) exposed to the solution and a density of SiO_(x) of2.2 g/cm3. FIG. 9 shows the predicted initial thickness of the SiO_(x)coating required, based on the conditions and assumptions of thisexample (assuming a residual SiO_(x) coating of at least 30 nm at theend of the desired shelf life of two years, and assuming storage at 20to 25° C.). As FIG. 9 shows, the predicted initial thickness of thecoating is about 36 nm at pH 5, about 80 nm at pH 6, about 230 nm at pH7, about 400 nm at pH 7.5, about 750 nm at pH 8, and about 2600 nm at pH9.

The coating thicknesses in FIG. 9 represent atypically harsh casescenarios for pharma and biotech products. Most biotech products andmany pharma products are stored at refrigerated conditions and none aretypically recommended for storage above room temperature. As a generalrule of thumb, storage at a lower temperature reduces the thicknessrequired, all other conditions being equivalent.

The following conclusions are reached, based on this test. First, theamount of dissolved Si in the SiO_(x) coating or glass increasesexponentially with increasing pH. Second, the SiO_(x) coating dissolvesmore slowly than borosilicate glass at a pH lower than 8. The SiO_(x)coating shows a linear, monophasic dissolution over time, whereasborosilicate glass tends to show a more rapid dissolution in the earlyhours of exposure to solutions, followed by a slower linear dissolution.This may be due to surface accumulation of some salts and elements onborosilicate during the forming process relative to the uniformcomposition of the SiO_(x) coating. This result incidentally suggeststhe utility of an SiO_(x) coating on the wall of a borosilicate glassvial to reduce dissolution of the glass at a pH lower than 8. Third,PECVD applied barrier coatings for vials in which pharmaceuticalpreparations are stored will need to be adapted to the specificpharmaceutical preparation and proposed storage conditions (or viceversa), at least in some instances in which the pharmaceuticalpreparation interacts with the barrier coating significantly.

Example 27

An experiment is conducted with vessels coated with SiO_(x)coating+OMCTS pH protective coating or layer, to test the pH protectivecoating or layer for its functionality as a protective coating or layer.The vessels are 5 mL vials (the vials are normally filled with productto 5 mL; their capacity without headspace, when capped, is about 7.5 mL)composed of cyclic olefin co-polymer (COC, Topas® 6013M-07).

Sixty vessels are coated on their interior surfaces with an SiO_(x)coating produced in a plasma enhanced chemical vapor deposition (PECVD)process using a HMDSO precursor gas according to the Protocol forCoating Tube Interior with SiO_(x) set forth above, except thatequipment suitable for coating a vial is used. The following conditionsare used.

-   -   HMDSO flow rate: 0.47 sccm    -   Oxygen flow rate: 7.5 sccm    -   RF power: 70 Watts    -   Coating time: 12 seconds (includes a 2-sec RF power ramp-up        time)

Next the SiO_(x) coated vials are coated over the SiO_(x) with anSiO_(x)C_(y) coating produced in a PECVD process using an OMCTSprecursor gas according to the Protocol for Coating COC Syringe BarrelInterior with OMCTS Lubricity Coating set forth above, except that thesame coating equipment is used as for the SiO_(x) coating. Thus, thespecial adaptations in the protocol for coating a syringe are not used.The following conditions are used.

-   -   OMCTS flow rate: 2.5 sccm    -   Argon flow rate: 10 sccm    -   Oxygen flow rate: 0.7 sccm    -   RF power: 3.4 Watts    -   Coating time: 5 seconds

Eight vials are selected and the total deposited quantity of PECVDcoating (SiO_(x)+SiO_(x)C_(y)) is determined with a Perkin Elmer OptimaModel 7300DV ICP-OES instrument, using the Protocol for Total SiliconMeasurement set forth above. This measurement determines the totalamount of silicon in both coatings, and does not distinguish between therespective SiO_(x) and SiO_(x)C_(y) coatings. The results are shownbelow.

Vial Total Silicon ug/L 1 13844 2 14878 3 14387 4 13731 5 15260 6 150177 15118 8 12736 Mean 14371 StdDev 877 Quantity of SiO_(x) + Lubricitylayer on Vials

In the following work, except as indicated otherwise in this example,the Protocol for Determining Average Dissolution Rate is followed. Twobuffered pH test solutions are used in the remainder of the experiment,respectively at pH 4 and pH 8 to test the effect of pH on dissolutionrate. Both test solutions are 50 mM buffers using potassium phosphate asthe buffer, diluted in water for injection (WFI) (0.1 um sterilized,filtered). The pH is adjusted to pH 4 or 8, respectively, withconcentrated nitric acid.

25 vials are filled with 7.5 ml per vial of pH 4 buffered test solutionand 25 other vials are filled with 7.5 ml per vial of pH 4 buffered testsolution (note the fill level is to the top of the vial—no head space).The vials are closed using prewashed butyl stoppers and aluminum crimps.The vials at each pH are split into two groups. One group at each pHcontaining 12 vials is stored at 4° C. and the second group of 13 vialsis stored at 23° C.

The vials are sampled at Days 1, 3, 6, and 8. The Protocol for MeasuringDissolved Silicon in a Vessel is used, except as otherwise indicated inthis example. The analytical result is reported on the basis of partsper billion of silicon in the buffered test solutions of each vial. Adissolution rate is calculated in terms of parts per billion per day asdescribed above in the Protocol for Determining Average DissolutionRate. The results at the respective storage temperatures follow:

Shelf Life Conditions 23° C. Vial SiO_(x) + Lubricity Vial SiO_(x) +Lubricity Coating at pH 4 Coating at pH 8 Si Dissolution Rate 31 7(PPB/day) Shelf Life Conditions 4° C. Vial SiO_(x) + Lubricity VialSiO_(x) + Lubricity Coating at pH 4 Coating at pH 8 Si Dissolution Rate7 11 (PPB/day)

The observations of Si dissolution versus time for the OMCTS-basedcoating at pH8 and pH 4 indicate the pH 4 rates are higher at ambientconditions. Thus, the pH 4 rates are used to determine how much materialwould need to be initially applied to leave a coating of adequatethickness at the end of the shelf life, taking account of the amount ofthe initial coating that would be dissolved. The results of thiscalculation are:

Vial SiO_(x) + Lubricity Coating at pH 4 Si Dissolution Rate (PPB/day)31 Mass of Coating Tested (Total Si) 14,371 Shelf Life (days) at 23° C.464 Shelf Life (years) at 23° C. 1.3 Required Mass of Coating (TotalSi) - 2 years 22,630 Required Mass of Coating (Total Si) - 3 years33,945Shelf Life Calculation

Based on this calculation, the OMCTS protective layer needs to be about2.5 times thicker—resulting in dissolution of 33945 ppb versus the14,371 ppb representing the entire mass of coating tested—to achieve a3-year calculated shelf life.

Example 28

The results of Comparative Example 26 and Example 27 above can becompared as follows, where the “pH protective coating or layer” is thecoating of SiO_(x)C_(y) referred to in Example BB.

Shelf Life Conditions - - pH 8 and 23° C. Vial SiO_(x) + Lubricity VialSiO_(x) Coating Si Dissolution Rate (PPB/day) 1,250 7

This data shows that the silicon dissolution rate of SiO_(x) alone isreduced by more than 2 orders of magnitude at pH 8 in vials also coatedwith SiO_(x)C_(y) coatings.

Example 29

Another comparison is shown by the following data from several differentexperiments carried out under similar accelerated dissolutionconditions, of which the 1-day data is also presented in FIG. 10.

Silicon Dissolution with pH 8 at 40° C. (ug/L) Vial Coating 1 2 3 4 7 1015 Description day days days days days days days A. SiO_(x) made withHMDSO 165 211 226 252 435 850 1,364 Plasma + Si_(w)O_(x)C_(y) or itsequivalent SiO_(x)C_(y) made with OMCTS Plasma B. Si_(w)O_(x)C_(y) orits 109 107 76 69 74 158 198 equivalent SiO_(x)C_(y) made with OMCTSPlasma C. SiO_(x) made with HMDSO 2,504 4,228 5,226 5,650 9,292 10,1779,551 Plasma D. SiO_(x) made with HMDSO 1,607 1,341 3,927 10,182 18,14820,446 21,889 Plasma + Si_(w)O_(x)C_(y) or its equivalent SiO_(x)C_(y)made with HMDSO Plasma E. Si_(w)O_(x)C_(y) or its 1,515 1,731 1,8131,743 2,890 3,241 3,812 equivalent SiO_(x)C_(y) made with HMDSO Plasma

FIG. 10 and Row A (SiO_(x) with OMCTS coating) versus C (SiO_(x) withoutOMCTS coating) show that the OMCTS pH protective coating or layer isalso an effective protective coating or layer to the SiO_(x) coating atpH 8. The OMCTS coating reduced the one-day dissolution rate from 2504μg/L (“u” or p or the Greek letter “mu” as used herein are identical,and are abbreviations for “micro”) to 165 ug/L. This data also showsthat an HMDSO-based Si_(w)O_(x)C_(y) (or its equivalent SiO_(x)C_(y))overcoat (Row D) provided a far higher dissolution rate than anOMCTS-based Si_(w)O_(x)C_(y) (or its equivalent SiO_(x)C_(y)) overcoat(Row A). This data shows that a substantial benefit can be obtained byusing a cyclic precursor versus a linear one.

Example 30

Samples 1-6 as listed in Table 9 were prepared as described in ExampleAA, with further details as follows.

A cyclic olefin copolymer (COC) resin was injection molded to form abatch of 5 ml vials. Silicon chips were adhered with double-sidedadhesive tape to the internal walls of the vials. The vials and chipswere coated with a two layer coating by plasma enhanced chemical vapordeposition (PECVD). The first layer was composed of SiO_(x) with barrierproperties as defined in the present disclosure, and the second layerwas an SiO_(x)C_(y) pH protective coating or layer.

A precursor gas mixture comprising OMCTS, argon, and oxygen wasintroduced inside each vial. The gas inside the vial was excited betweencapacitively coupled electrodes by a radio-frequency (13.56 MHz) powersource. The monomer flow rate (Fm) in units of sccm, oxygen flow rate(Fo) in units of sccm, argon flowrate in sccm, and power (W) in units ofwatts are shown in Table 9.

A composite parameter, W/FM in units of kJ/kg, was calculated fromprocess parameters W, Fm, Fo and the molecular weight, M in g/mol, ofthe individual gas species. W/FM is defined as the energy input per unitmass of polymerizing gases. Polymerizing gases are defined as thosespecies that are incorporated into the growing coating such as, but notlimited to, the monomer and oxygen. Non-polymerizing gases, by contrast,are those species that are not incorporated into the growing coating,such as but not limited to argon, helium and neon.

In this test, PECVD processing at high W/FM is believed to have resultedin higher monomer fragmentation, producing organosiloxane coatings withhigher cross-link density. PECVD processing at low W/FM, by comparison,is believed to have resulted in lower monomer fragmentation producingorganosiloxane coatings with a relatively lower cross-link density.

The relative cross-link density of samples 5, 6, 2, and 3 was comparedbetween different coatings by measuring FTIR absorbance spectra. Thespectra of samples 5, 6, 2, and 3 are provided in FIGS. 13 to 16. Ineach spectrum, the ratio of the peak absorbance at the symmetricstretching mode (1000-1040 cm-1) versus the peak absorbance at theasymmetric stretching mode (1060-1100 cm-1) of the Si—O—Si bond wasmeasured, and the ratio of these two measurements was calculated, all asshown in Table 9. The respective ratios were found to have a linearcorrelation to the composite parameter W/FM as shown in FIG. 11.

A qualitative relation—whether the coating appeared oily (shiny, oftenwith irridescence) or non-oily (non-shiny) when applied on the siliconchips—was also found to correlate with the W/FM values in Table 9. Oilyappearing coatings deposited at lower W/FM values, as confirmed by Table9, are believed to have a lower crosslink density, as determined bytheir lower sym/asym ratio, relative to the non-oily coatings that weredeposited at higher W/FM and a higher cross-link density. The onlyexception to this general rule of thumb was sample 2 in Table 9. It isbelieved that the coating of sample 2 exhibited a non-oily appearancebecause it was was too thin to see. Thus, an oilyness observation wasnot reported in Table 9 for sample 2. The chips were analyzed by FTIR intransmission mode, with the infrared spectrum transmitted through thechip and sample coating, and the transmission through an uncoated nullchip subtracted.

Non-oily organosiloxane layers produced at higher W/FM values, whichprotect the underlying SiO_(x) coating from aqueous solutions atelevated pH and temperature, were preferred because they provided lowerSi dissolution and a longer shelf life, as confirmed by Table 9. Forexample, the calculated silicon dissolution by contents of the vial at apH of 8 and 40° C. was reduced for the non-oily coatings, and theresulting shelf life was 1381 days in one case and 1147 days in another,as opposed to the much shorter shelf lives and higher rates ofdissolution for oily coatings. Calculated shelf life was determined asshown for Example AA. The calculated shelf life also correlated linearlyto the ratio of symmetric to asymmetric stretching modes of the Si—O—Sibond in organosiloxane pH protective coatings or layers.

Sample 6 can be particularly compared to Sample 5. An organosiloxane, pHprotective coating or layer was deposited according to the processconditions of sample 6 in Table 9. The coating was deposited at a highW/FM. This resulted in a non-oily coating with a high Si—O—Si sym/asymratio of 0.958, which resulted in a low rate of dissolution of 84.1ppb/day (measured by the Protocol for Determining Average DissolutionRate) and long shelf life of 1147 days (measured by the Protocol forDetermining Calculated Shelf Life). The FTIR spectra of this coating isshown in FIG. 35, which exhibits a relatively similar asymmetric Si—O—Sipeak absorbance compared to the symmetric Si—O—Si peak absorbance. Thisis an indication of a higher cross-link density coating, which is apreferred characteristic for pH protection and long shelf life.

An organosiloxane pH protective coating or layer was deposited accordingto the process conditions of sample 5 in Table 9. The coating wasdeposited at a moderate W/FM. This resulted in an oily coating with alow Si—O—Si sym/asym ratio of 0.673, which resulted in a high rate ofdissolution of 236.7 ppb/day (following the Protocol for DeterminingAverage Dissolution Rate) and shorter shelf life of 271 days (followingthe Protocol for Determining Calculated Shelf Life). The FTIR spectrumof this coating is shown in FIG. 13, which exhibits a relatively highasymmetric Si—O—Si peak absorbance compared to the symmetric Si—O—Sipeak absorbance. This is an indication of a lower cross-link densitycoating, which is contemplated in any embodiment to be an unfavorablecharacteristic for pH protection and long shelf life.

Sample 2 can be particularly compared to Sample 3. A pH protectivecoating or layer was deposited according to the process conditions ofsample 2 in Table 9. The coating was deposited at a low W/FM. Thisresulted in a coating that exhibited a low Si—O—Si sym/asym ratio of0.582, which resulted in a high rate of dissolution of 174 ppb/day andshort shelf life of 107 days. The FTIR spectrum of this coating is shownin FIG. 36, which exhibits a relatively high asymmetric Si—O—Si peakabsorbance compared to the symmetric Si—O—Si peak absorbance. This is anindication of a lower cross-link density coating, which is anunfavorable characteristic for pH protection and long shelf life.

An organosiloxane, pH pH protective coating or layer was depositedaccording to the process conditions of sample 3 in Table 9. The coatingwas deposited at a high W/FM. This resulted in a non-oily coating with ahigh Si—O—Si sym/asym ratio of 0.947, which resulted in a low rate of Sidissolution of 79.5 ppb/day (following the Protocol for DeterminingAverage Dissolution Rate) and long shelf life of 1381 days (followingthe Protocol for Determining Calculated Shelf Life). The FTIR spectrumof this coating is shown in FIG. 37, which exhibits a relatively similarasymmetric Si—O—Si peak absorbance compared to the symmetric Si—O—Sipeak absorbance. This is an indication of a higher cross-link densitycoating, which is a preferred characteristic for pH protection and longshelf life.

TABLE 9 FTIR Absorbance Process Parameters Si Dissoution @ pH 8/40^(°)C. Si—O—Si Si—O—Si Flow O₂ Total Shelf Rate of sym stretch asym stretchRatio Rate Flow Power W/FM Si life Dissolution (1000- (1160- Si—O—SiSamples OMCTS Ar Rate (W) (kJ/kg) (ppb) (days) (ppb/day) 1040 cm⁻¹) 1100cm⁻¹) (sym/asym) Oilyness 1 3 10 0.5 14 21613 43464 385 293.18 0.1530.219 0.700 YES 2 3 20 0.5 2 3088 7180 107 174.08 0.011 0.020 0.582 NA 31 20 0.5 14 62533 42252.17 1381 79.53 0.093 0.098 0.947 NO 4 2 15 0.5 818356 27398 380 187.63 0.106 0.141 0.748 YES 5 3 20 0.5 14 21613 24699271 236.73 0.135 0.201 0.673 YES 6 1 10 0.5 14 62533 37094 1147 84.10.134 0.140 0.958 NO

Example 31

An experiment similar to Example 27 was carried out, modified asindicated in this example and in Table 10 (where the results aretabulated). 100 5 mL COP vials were made and coated with an SiO_(x)barrier layer and an OMCTS-based pH protective coating or layer asdescribed previously, except that for Sample PC194 only the pHprotective coating or layer was applied. The coating quantity was againmeasured in parts per billion extracted from the surfaces of the vialsto remove the entire pH protective coating or layer, as reported inTable 10.

In this example, several different coating dissolution conditions wereemployed. The test solutions used for dissolution contained either 0.02or 0.2 wt. % polysorbate-80 surfactant, as well as a buffer to maintaina pH of 8. Dissolution tests were carried out at either 23° C. or 40° C.

Multiple syringes were filled with each test solution, stored at theindicated temperature, and analyzed at several intervals to determinethe extraction profile and the amount of silicon extracted. An averagedissolution rate for protracted storage times was then calculated byextrapolating the data obtained according to the Protocol forDetermining Average Dissolution Rate. The results were calculated asdescribed previously and are shown in Table 10. Of particular note, asshown on Table 10, were the very long calculated shelf lives of thefilled packages provided with a PC 194 pH protective coating or layer:

21045 days (over 57 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 23° C.;

38768 days (over 100 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 23° C.;

8184 days (over 22 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 40° C.; and

14732 days (over 40 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 40° C.

Referring to Table 10, the longest calculated shelf lives correspondedwith the use of an RF power level of 150 Watts and a corresponding highW/FM value. It is believed that the use of a higher power level causeshigher cross-link density of the pH protective coating or layer.

TABLE 10 OMCTS Argon O₂ Plasma Total Si Calculated Average Rate FlowRate Flow Rate Flow Rate Power Duration W/FM (PPb) (OMCTS) Shelf-life ofDissolution Sample (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) layer) (days)(ppb/day) Process Parameters Si Dissolution @ pH 8/23^(°) C./0.02%Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 21045 3.5 018 1.0 200.5 18 15 77157 42982 1330 32.3 Process Parameters Si Dissolution @ pH8/23^(°) C./0.2% Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 387681.9 018 1.0 20 0.5 18 15 77157 42982 665 64.6 048 4 80 2 35 20 3750756520 1074 52.62 Process Parameters Si Dissolution @ pH 8/40^(°)C./0.02% Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 8184 9 018 1.020 0.5 18 15 77157 42982 511 84 Process Parameters Si Dissolution @ pH8/40^(°) C./0.2% Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 147325 018 1.0 20 0.5 18 15 77157 42982 255 168

Example 32

Another series of experiments similar to those of Example 31 are run,showing the effect of progressively increasing the RF power level on theFTIR absorbance spectrum of the pH protective coating or layer. Theresults are tabulated in Table 11, which in each instance shows asymmetric/assymmetric ratio greater than 0.75 between the maximumamplitude of the Si—O—Si symmetrical stretch peak normally locatedbetween about 1000 and 1040 cm-1, and the maximum amplitude of theSi—O—Si assymmetric stretch peak normally located between about 1060 andabout 1100 cm-1. Thus, the symmetric/assymmetric ratio is 0.79 at apower level of 20 W, 1.21 or 1.22 at power levels of 40, 60, or 80 W,and 1.26 at 100 Watts under otherwise comparable conditions.

The 150 Watt data in Table 11 is taken under somewhat differentconditions than the other data, so it is not directly comparable withthe 20-100 Watt data discussed above. The FTIR data of samples 6 and 8of Table 11 was taken from the upper portion of the vial and the FTIRdata of samples 7 and 9 of Table 11 was taken from the lower portion ofthe vial. Also, the amount of OMCTS was cut in half for samples 8 and 9of Table 11, compared to samples 6 and 7. Reducing the oxygen levelwhile maintaining a power level of 150 W raised the symmetric/asymmetricratio still further, as shown by comparing samples 6 and 7 to samples 8and 9 in Table 11.

It is believed that, other conditions being equal, increasing thesymmetric/asymmetric ratio increases the shelf life of a vessel filledwith a material having a pH exceeding 5.

Table 12 shows the calculated O-Parameters and N-Parameters (as definedin U.S. Pat. No. 8,067,070) for the experiments summarized in Table 11.As Table 12 shows, the O-Parameters ranged from 0.134 to 0.343, and theN-Parameters ranged from 0.408 to 0.623—all outside the ranges claimedin U.S. Pat. No. 8,067,070.

TABLE 11 Sym- Assym- OMCTS Argon O₂ Plasma metric Stretch etricStretchSymmetric/ Flow Rate Flow Rate Flow Rate Power Duration W/FM Peak at1000- Peak at 1060- Assymetric Samples (sccm) (sccm) (sccm) (W) (sec)(kJ/kg) 1040 cm−¹ 1100 cm−¹ Ratio ID Process Parameters FTIR Results 1 120 0.5 20 20 85,730 0.0793 0.1007 0.79 2 1 20 0.5 40 20 171,460 0.06190.0507 1.22 3 1 20 0.5 60 20 257,190 0.1092 0.0904 1.21 4 1 20 0.5 80 20342,919 0.1358 0.1116 1.22 5 1 20 0.5 100 20 428,649 0.209 0.1658 1.26 61 20 0.5 150 20 642,973 0.2312 0.1905 1.21 7 1 20 0.5 150 20 642,9730.2324 0.1897 1.23 8 0.5 20 0.5 150 20 1,223,335 0.1713 0.1353 1.27 90.5 20 0.5 150 20 1,223,335 0.1475 0.1151 1.28

TABLE 12 OMCTS Argon O₂ Plasma Samples Flow Rate Flow Rate Flow RatePower Duration W/FM O- N- ID (sccm) (sccm) (sccm) (W) (sec) (kJ/kg)Parameter Parameter Process Parameters 1 1 20 0.5 20 20 85,730 0.3430.436 2 1 20 0.5 40 20 171,460 0.267 0.408 3 1 20 0.5 60 20 257,1900.311 0.457 4 1 20 0.5 80 20 342,919 0.270 0.421 5 1 20 0.5 100 20428,649 0.177 0.406 6 1 20 0.5 150 20 642,973 0.151 0.453 7 1 20 0.5 15020 642,973 0.151 0.448 8 0.5 20 0.5 150 20 1,223,335 0.134 0.623 9 0.520 0.5 150 20 1,223,335 0.167 0.609

Example 33

The purpose of this example was to evaluate the recoverability ordrainage of a slightly viscous aqueous solution from glass, COP andcoated vials,

This study evaluated the recovery of a 30 cps (centipoise) carbohydratesolution in water-for-injection from (A) an uncoated COP vial, (B) anSiO_(x)+pH protective layer coated COP vial prepared according to theabove Protocol for Coating Syringe Barrel Interior with SiO_(x),followed by the Protocol for Coating Syringe Barrel Interior with OMCTSPH protective Coating or Layer, and (C) a glass vial.

2.0 ml of the carbohydrate solution was pipetted into 30 vials each ofglass, COP and pH protective coated vials. The solution was aspiratedfrom the vials with a 10 ml syringe, through a 23 gauge, 1.5″ needle.The vials were tipped to one side as the solution was aspirated tomaximize the amount recovered. The same technique and similar withdrawaltime was used for all vials. The vials were weighed empty, after placing2.0 ml of the solution to the vial and at the conclusion of aspiratingthe solution from the vial. The amount delivered to the vial (A) wasdetermined by subtracting the weight of the empty vial from the weightof the vial with the 2.0 ml of solution. The weight of solution notrecovered (B) was determined by subtracting the weight of the empty vialfrom the weight of the vials after aspirating the solution from thevial. The percent unrecovered was determined by dividing B by A andmultiplying by 100.

It was observed during the aspiration of drug product that the glassvials remained wetted with the solution. The COP vial repelled theliquid and as the solution was aspirated from the vials. This helpedwith recovery but droplets were observed to bead on the sidewalls of thevials during the aspiration. The pH protective coated vials alsorepelled the liquid during aspiration but no beading of solution on thesidewalls was observed.

The conclusion was that pH protective coated vials do not wet withaqueous solutions as do glass vials, leading to superior recovery ofdrug product relative to glass. PH protective coated vials were notobserved to cause beading of solution on sidewall during aspiration ofaqueous products therefore coated vials performed better than uncoatedCOP vials in product recovery experiments.

Example 34

Syringe samples were produced as follows. A COC 8007 extended barrelsyringe was produced according to the Protocol for Forming COC SyringeBarrel. An SiO_(x) coating or layer was applied to some of the syringesaccording to the Protocol for coating COC Syringe Barrel Interior withSiO_(x). A pH protective coating or layer was applied to the SiO_(x)coated syringes according to the Protocol for Coating COC Syringe BarrelInterior with OMCTS Lubricity Coating, modified as follows. The OMCTSwas supplied from a vaporizer, due to its low volatility. Argon carriergas was used. The process conditions were set to the following:

-   -   OMCTS—3 sccm    -   Argon gas—65 sccm    -   Power—6 watts    -   Time—10 seconds

The coater was later determined to have a small leak while producing thesamples identified in the Table, which resulted in an estimated oxygenflow of 1.0 sccm. The samples were produced without introducing oxygen.

The coatings produced according to these working examples arecontemplated to function as primer coatings or layers, and also asprotective coatings or layers to increase the shelf life of the vessels,compared to similar vessels provided with a barrier coating or layer butno pH protective coating or layer.

PECVD Process for Trilayer Coating

The PECVD trilayer coating described in this specification can beapplied, for example, as follows for a 1 to 5 mL vessel. Two specificexamples are 1 mL thermoplastic resin syringe and a 5 mL thermoplasticresin drug vial. Larger or smaller vessels will call for adjustments inparameters that a person of ordinary skill can carry out in view of theteaching of this specification.

The apparatus used is the PECVD apparatus with rotating quadrupolemagnets as described generally in this specification.

The general coating parameter ranges, with preferred ranges inparentheses, for a trilayer coating for a 1 mL syringe barrel are shownin the PECVD Trilayer Process General Parameters Tables (1 mL syringeand 5 mL vial).

PECVD Trilayer Process General Parameters Table (1 mL syringe) ParameterUnits Tie Barrier pH Protective Power W 40-90 140 40-90 (60-80) (60-80)TMDSO Flow sccm  1-10 None  1-10 (3-5) (3-5) HMDSO Flow sccm None 1.56None O₂ Flow sccm 0.5-5  20 0.5-5  (1.5-2.5) (1.5-2.5) Argon Flow sccm 40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None None NoneDeposition Time seconds 0.1-10  20 0.1-40  (1-3) (15-25) Tube PressureTorr 0.01-10  0.59 0.01-10  (0.1-1.5) (0.1-1.5)

PECVD Trilayer Process General Parameters Table (5 mL vial) ParameterUnits Adhesion Barrier Protection Power W 40-90 140 40-90 (60-80)(60-80) TMDSO Flow sccm  1-10 None  1-10 (3-5) (3-5) HMDSO Flow sccmNone 1.56 None O₂ Flow sccm 0.5-5  20 0.5-5  (1.5-2.5) (1.5-2.5) ArgonFlow sccm  40-120 0  40-120 (70-90) (70-90) Ramp Time seconds None NoneNone Deposition Time seconds 0.1-10  20 0.1-40  (1-3) (15-25) TubePressure Torr 0.01-10  0.59 0.01-10  (0.1-1.5) (0.1-1.5)

Example 35

Examples of specific coating parameters that have been used for a 1 mLsyringe and 5 mL vial are shown in the PECVD Trilayer Process SpecificParameters Tables (1 mL syringe and 5 mL vial):

PECVD Trilayer Process Specific Parameters Table (1 mL syringe)Parameter Units Tie Barrier Protection Power W 70 140 70 TMDSO Flow sccm4 None 4 HMDSO Flow sccm None 1.56 None O₂ Flow sccm 2 20 2 Argon Flowsccm 80 0 80 Ramp Time seconds None None None Deposition Time seconds2.5 20 10 Tube Pressure Torr 1 0.59 1

PECVD Trilayer Process Specific Parameters Table (5 mL vial) ParameterUnits Adhesion Barrier Protection Power W 20 40 20 TMDSO Flow sccm 2 0 2HMDSO Flow sccm 0 3 0 O₂ Flow sccm 1 50 1 Argon Flow sccm 20 0 20 RampTime seconds 0 2 2 Deposition Time seconds 2.5 10 10 Tube Pressure Torr0.85 1.29 0.85

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 1 mL syringe as described above are 0.34 and 0.55,respectively.

The O-parameter and N-parameter values for the pH protective coating orlayer applied to the 5 mL vial are 0.24 and 0.63, respectively.

Example 36

Referring to FIG. 18 and Table, Example 36, the thickness uniformity atfour different points along the length of a 1 mL syringe with a stakedneedle (present during PECVD deposition) and the indicated trilayercoating (avg. thicknesses: 38 nm adhesion or tie coating or layer; 55 nmbarrier coating or layer, 273 nm pH protective coating or layer) isshown. The table shows individual layer thicknesses at the four markedpoints, showing adequate thickness of each layer at each point along thehigh profile syringe barrel.

TABLE Example 36 Syringe Location Adhesion Barrier Protection 1 46 75343 2 38 55 273 3 86 47 493 4 42 25 287

Referring to FIG. 19, the plot maps the coating thickness over theportion of the cylindrical inner surface of the barrel shown in FIG. 18,as though unrolled to form a rectangle. The overall range of thicknessof the trilayer coating is 572 plus or minus 89 nm.

FIG. 20 is a photomicrograph showing a cross-section of the trilayercoating on a COP syringe substrate at the point 2 shown in FIG. 18.

A syringe having a coating similar to the trilayer coating of FIGS.18-20 is tested for shelf life, using the silicon dissolution andextrapolation method described in this specification, compared tosyringes having a bilayer coating (similar to the trilayer coatingexcept lacking the tie coating or layer) and a monolayer coating whichis just the pH protective coating or layer directly applied to thethermoplastic barrel of the syringe, with no barrier layer. The testsolution was a 0.2% Tween, pH 8 phosphate buffer. The extrapolated shelflives of the monolayer and trilayer coatings were similar and verylong—on the order of 14 years. The shelf life of the syringes having abilayer coating were much lower—less than two years. In other words, thepresence of a barrier layer under the pH protective layer shortened theshelf life of the coating substantially, but the shelf life was restoredby providing a tie coating or layer under the barrier layer, sandwichingthe barrier coating or layer with respective SiO_(x)C_(y) layers. Thebarrier layer is necessary to establish a gas barrier, so the monolayercoating would not be expected to provide adequate gas barrier propertiesby itself. Thus, only the trilayer coating had the combination of gasbarrier properties and a long shelf life, even while in contact with asolution that would attack an exposed barrier coating or layer.

Example 37

FIGS. 21 and 22 show a trilayer coating distribution for the 5 mL vial,which is much shorter in relation to its inner diameter and thus easierto coat uniformly, showing very little variation in coating thickness,with the great majority of the surface coated between 150 and 250 nmthickness of the trilayer, with only a small proportion of the containercoated with between 50 and 250 nm of the trilayer.

Example 38

FIG. 23 shows the breakdown of coating thickness (nm) by vial location.The Vial Coating Distribution Table shows the uniformity of coating.

Vial Coating Distribution Table Vial Location Adhesion BarrierProtection Total Trilayer, nm 1 13 29 77 119 2 14 21 58 93 3 25 37 115177 4 35 49 158 242 5 39 49 161 249 6 33 45 148 226 7 31 29 153 213 8 4816 218 282 9 33 53 155 241 10 31 29 150 210 Average 30 36 139 205

Example 39

FIG. 24 is a visual test result showing the integrity of the trilayervial coating described above. The three 5 mL cyclic olefin polymer (COC)vials of FIGS. 24 and 24A were respectively:

-   -   uncoated (left vial),    -   coated with the bilayer coating described in this specification        (a barrier coating or layer plus a pH protective coating or        layer—the second and third components of the trilayer coating)        (center vial); and    -   coated with the trilayer coating as described above (right        vial).

The three vials were each exposed to 1 N potassium hydroxide for fourhours, then exposed for 24 hours to a ruthenium oxide (RuO4) stain thatdarkens any exposed part of the thermoplastic vial unprotected by thecoatings. The high pH potassium hydroxide exposure erodes any exposedpart of the barrier coating or layer at a substantial rate, greatlyreduced, however by an intact pH protective coating or layer. Inparticular, the high pH exposure opens up any pinholes in the coatingsystem. As FIG. #24 shows, the uncoated vial is completely black,showing the absence of any effective coating. The bilayer coating wasmostly intact under the treatment conditions, but on microscopicinspection has many pinholes (illustrated by FIG. 24A) where theruthenium stain reached the thermoplastic substrate through the coating.The overall appearance of the bilayer coating clearly shows visible“soiled” areas where the stain penetrated. The trilayer coating,however, protected the entire vial against penetration of the stain, andthe illustrated vial remains clear after treatment. This is believed tobe the result of sandwiching the barrier coating or layer between twolayers of SiO_(x)C_(y), which both protects the barrier layer againstdirect etching and against undercutting and removal of flakes of thebarrier layer.

The invention claimed is:
 1. A vessel comprising: a thermoplastic wallhaving an interior surface enclosing at least a portion of a lumen; atie coating or layer comprising SiO_(x)C_(y)H_(z) or SiN_(x)C_(y)H_(z)in which x is from 0.5 to 2.4 as measured by X-ray photoelectronspectroscopy (XPS), y is from 0.6 to 3 as measured by XPS, and z is from2 to 9 as measured by Rutherford backscattering spectrometry (RBS), thetie coating or layer having an outer surface facing the interior surfaceof the thermoplastic wall and the tie coating or layer having aninterior surface; a barrier coating or layer of SiO_(x), in which x isfrom 1.5 to 2.9 as measured by XPS, the barrier coating or layerpositioned between the interior surface of the tie coating or layer andthe lumen; and a pH protective coating or layer of SiO_(x)C_(y)H_(z), inwhich x is from 0.5 to 2.4 as measured by XPS, y is from 0.6 to 3 asmeasured by XPS, and z is from 2 to 9 as measured by RBS, positionedbetween the barrier coating or layer and the lumen, in which an FTIRabsorbance spectrum of the pH protective coating or layer has a ratiogreater than 0.9 between: the maximum amplitude of the Si-O-Sisymmetrical stretch peak between 1000 and 1040 cm⁻¹, and the maximumamplitude of the Si-O-Si asymmetric stretch peak between 1060 and 1100cm⁻¹; in which the silicon dissolution rate by a 50 mM potassiumphosphate buffer diluted in water for injection, adjusted to pH 8 withconcentrated nitric acid, and containing 0.2 wt. % polysorbate-80surfactant, from the vessel is less than 170 ppb/day.
 2. The vessel ofclaim 1, in which at least one of the tie coating or layer, the barriercoating or layer, or the pH protective coating or layer is applied byplasma enhanced chemical vapor deposition (PECVD).
 3. The vessel ofclaim 1, which is a syringe barrel, a vial, a cartridge or a blisterpackage.
 4. The vessel of claim 1, in which at least a portion of thethermoplastic wall comprises: a polyolefin a polyvinylalcohol apolymethacrylate ether a polyacrylic acid a polyamide a polyimide apolysulfone a polylactic acid a cyclic olefin polymer or copolymer apolyester or a combination of a polyolefin and a polyester.
 5. Thevessel of claim 1, in which, for at least one of the pH protectivecoating or layer or the tie coating or layer, x is from 1 to 2 asmeasured by XPS, y is from 0.6 to 1.5 as measured by XPS, and z is from2 to 5 as measured by RBS.
 6. The vessel of claim 1, in which the pHprotective coating or layer is from 10 to 1000 nm thick.
 7. The vesselof claim 1, in which the rate of erosion of the pH protective coating orlayer, if directly contacted by a fluid contained in the lumen having apH greater than 5, is less than 20% of the rate of erosion of thebarrier coating or layer, if directly contacted by the same fluid underthe same conditions.
 8. The vessel of claim 1, having a shelf life,while directly contacted by a fluid contained in the lumen having a pHgreater than 5, of at least two years, based on storage of the vesselcontaining the fluid at 20° C.
 9. The vessel of claim 1, in which afluid contained in the lumen having a pH greater than 5 removes the pHprotective coating or layer at a rate of 1 nm or less of pH protectivecoating or layer thickness per 88 hours of contact with the fluid. 10.The vessel of claim 1, wherein the pH protective coating or layer showsan O-Parameter measured with attenuated total reflection (ATR) of lessthan 0.4, measured as:${O\text{-}{Parameter}} = \frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}^{- 1}}{{Maximum}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu}{from}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{{cm}^{- 1}.}}$11. The vessel of claim 1, in which the tie coating or layer has anaverage thickness from 5 to 200 nm.
 12. The vessel of claim 1, which isa prefilled syringe having a syringe barrel coated on its interior wallwith the tie coating or layer, barrier coating or layer, and pHprotective coating or layer, further having a plunger seated in thebarrel and containing a pharmaceutical composition having a pH greaterthan 5 contained in the lumen, the prefilled syringe having a shelf lifeof at least six months.
 13. A process for making a vessel according toclaim 1, the process comprising the steps: forming a tie coating orlayer; forming a barrier coating or layer; and forming a pH protectivecoating or layer positioned between the barrier coating or layer and thelumen, the pH protective coating or layer and tie coating or layertogether being effective to keep the barrier coating or layer at leastsubstantially undissolved as a result of attack by a fluid contained inthe lumen having a pH greater than 5 for a period of at least sixmonths.